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McTaggart T, Lim JX, Smith KJ, Heaney B, McDonald D, Hulme G, Hussain R, Coxhead J, Mann DA, Sayer AA, Granic A, Amarnath S. Deciphering Novel Communication Patterns in T Regulatory Cells From Very Old Adults. Aging Cell 2025:e70044. [PMID: 40100045 DOI: 10.1111/acel.70044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 01/30/2025] [Accepted: 02/26/2025] [Indexed: 03/20/2025] Open
Abstract
Regulatory T cells (Tregs) are important in maintaining tolerance and are key players in immunity. In aging, increased Treg function along with low-grade inflammation has been reported. This dichotomy of enhanced Treg function along with inflammation highlights the importance of understanding Treg biology and communication patterns in the very old. In this proof-of-concept study, we demonstrate that aged Tregs (85 years) do not significantly communicate with CD4+ and CD8+ T effectors when compared with healthy < 66-year-olds. Of note was the enhanced communication of aged Tregs with CD3+CD8+CD56+CD161- NK-like T-cell populations, which are important in antitumor and chronic viral diseases in older individuals. We found that in turn this population of killer-like T cells showed diminished cytotoxic characteristics, and killer receptor expression. Taken together, our proof-of-concept study delineates the biology of Tregs and identifies previously undefined communication patterns in the very old.
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Affiliation(s)
- Tegan McTaggart
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
- Centre for Cancer Research, The Medical School, Newcastle University, Newcastle Upon Tyne, UK
| | - Jing Xuan Lim
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
- Centre for Cancer Research, The Medical School, Newcastle University, Newcastle Upon Tyne, UK
| | - Katie J Smith
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
- Centre for Cancer Research, The Medical School, Newcastle University, Newcastle Upon Tyne, UK
| | - Bronagh Heaney
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
| | - David McDonald
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Gillian Hulme
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Rafiqul Hussain
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Jonathan Coxhead
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Derek A Mann
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- Centre for Cancer Research, The Medical School, Newcastle University, Newcastle Upon Tyne, UK
| | - Avan A Sayer
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
- AGE Research Group, Translational and Clinical Research Institute, Newcastle Upon Tyne, UK
| | - Antoneta Granic
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
- AGE Research Group, Translational and Clinical Research Institute, Newcastle Upon Tyne, UK
| | - Shoba Amarnath
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
- NIHR, Biomedical Research Centre, Newcastle Upon Tyne, UK
- Centre for Cancer Research, The Medical School, Newcastle University, Newcastle Upon Tyne, UK
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Weinstein KN, Domeier PP, Ziegler SF. A splice of life: the discovery, function, and clinical implications of FOXP3 isoforms in autoimmune disease. Int Immunol 2024; 37:83-90. [PMID: 39136284 DOI: 10.1093/intimm/dxae049] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/12/2024] [Indexed: 12/28/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in the development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.
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Affiliation(s)
- Kristin N Weinstein
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Phillip P Domeier
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA
| | - Steven F Ziegler
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA
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Wendering DJ, Amini L, Schlickeiser S, Farrera-Sal M, Schulenberg S, Peter L, Mai M, Vollmer T, Du W, Stein M, Hamm F, Malard A, Castro C, Yang M, Ranka R, Rückert T, Durek P, Heinrich F, Gasparoni G, Salhab A, Walter J, Wagner DL, Mashreghi MF, Landwehr-Kenzel S, Polansky JK, Reinke P, Volk HD, Schmueck-Henneresse M. Effector memory-type regulatory T cells display phenotypic and functional instability. SCIENCE ADVANCES 2024; 10:eadn3470. [PMID: 39231218 PMCID: PMC11421655 DOI: 10.1126/sciadv.adn3470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/30/2024] [Indexed: 09/06/2024]
Abstract
Regulatory T cells (Treg cells) hold promise for sustainable therapy of immune disorders. Recent advancements in chimeric antigen receptor development and genome editing aim to enhance the specificity and function of Treg cells. However, impurities and functional instability pose challenges for the development of safe gene-edited Treg cell products. Here, we examined different Treg cell subsets regarding their fate, epigenomic stability, transcriptomes, T cell receptor repertoires, and function ex vivo and after manufacturing. Each Treg cell subset displayed distinct features, including lineage stability, epigenomics, surface markers, T cell receptor diversity, and transcriptomics. Earlier-differentiated memory Treg cell populations, including a hitherto unidentified naïve-like memory Treg cell subset, outperformed late-differentiated effector memory-like Treg cells in regulatory function, proliferative capacity, and epigenomic stability. High yields of stable, functional Treg cell products could be achieved by depleting the small effector memory-like Treg cell subset before manufacturing. Considering Treg cell subset composition appears critical to maintain lineage stability in the final cell product.
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Affiliation(s)
- Désirée Jacqueline Wendering
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Leila Amini
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Stephan Schlickeiser
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- CheckImmune GmbH, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Martí Farrera-Sal
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Sarah Schulenberg
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Einstein Center for Regenerative Therapies at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Lena Peter
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Einstein Center for Regenerative Therapies at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Marco Mai
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Tino Vollmer
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Weijie Du
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Maik Stein
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Frederik Hamm
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Alisier Malard
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Carla Castro
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Mingxing Yang
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ramon Ranka
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Timo Rückert
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Pawel Durek
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Frederik Heinrich
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Gilles Gasparoni
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Abdulrahman Salhab
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Jörn Walter
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Dimitrios Laurin Wagner
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Transfusion Medicine, Charitéplatz 1, 10117 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Hannover Medical School, Department of Pediatric Pulmonology, Allergy and Neonatology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Julia K Polansky
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Hans-Dieter Volk
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- CheckImmune GmbH, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Michael Schmueck-Henneresse
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
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4
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Koumpis E, Papoudou-Bai A, Papathanasiou K, Kolettas E, Kanavaros P, Hatzimichael E. Unraveling the Immune Microenvironment in Diffuse Large B-Cell Lymphoma: Prognostic and Potential Therapeutic Implications. Curr Issues Mol Biol 2024; 46:7048-7064. [PMID: 39057061 PMCID: PMC11276293 DOI: 10.3390/cimb46070420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
Diffuse large B cell lymphoma (DLBCL) is a multifaceted condition characterized by significant diversity in its molecular and pathological subtypes and clinical manifestation. Despite the progress made in the treatment of DLBCL through the development of novel drugs, an estimated one-third of patients encounter relapse or acquire refractory disease. The tumor microenvironment (TME) of DLBCL, a complex network consisting of cellular and noncellular components that engage in interactions with the tumor, is a parameter that is gaining increasing attention. The TME comprises both the immune and nonimmune microenvironments. The immune microenvironment comprises natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), neutrophils, myeloid-derived suppressor cells (MDSCs), and T and B lymphocytes. The nonimmune microenvironment consists of the extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), mesenchymal stromal cells, and other molecules that are secreted. Despite ongoing research, the exact impact of these components and their interaction on the progression of the disease remains elusive. A comprehensive review of significant discoveries concerning the cellular and noncellular constituents, molecular characteristics, and treatment response and prognosis of the TME in DLBCL, as well as the potential targeting of the TME with novel therapeutic approaches, is provided in this article.
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Affiliation(s)
- Epameinondas Koumpis
- Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece; (E.K.); (K.P.)
| | - Alexandra Papoudou-Bai
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece;
| | - Konstantina Papathanasiou
- Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece; (E.K.); (K.P.)
| | - Evangelos Kolettas
- Laboratory of Biology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 110 Ioannina, Greece;
- Biomedical Research Institute, Foundation for Research and Technology, 45 110 Ioannina, Greece
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 110 Ioannina, Greece;
| | - Eleftheria Hatzimichael
- Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece; (E.K.); (K.P.)
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Soongsathitanon J, Homjan T, Pongcharoen S. Characteristic features of in vitro differentiation of human naïve CD4 + T cells to induced regulatory T cells (iTreg) and T helper (Th) 17 cells: Sharing of lineage-specific markers. Heliyon 2024; 10:e31394. [PMID: 38807879 PMCID: PMC11130651 DOI: 10.1016/j.heliyon.2024.e31394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/30/2024] Open
Abstract
In vitro induced regulatory T cells (iTreg) and IL-17 producing T cells (Th17-like cells) can be generated in culture from native CD4+ T cells in peripheral blood by different sets of cytokines. In the presence of transforming growth factor (TGF)-β plus interleukin (IL)-2, cells differentiate into Treg cells with increased expression of the forkhead box P3 (FOXP3). In the presence of TGF-β, IL-6, IL-1β and IL-23, cells differentiate into Th17 cells that produce IL-17A. However, protocols for the generation of human iTreg and Th17 are still controversial. In this study, we characterized the biological features of iTreg and Th17 cells differentiated from peripheral blood naïve CD4+ T cells in vitro using the established protocols. We showed that cells obtained from Treg or Th17 culture conditions shared some phenotypic markers. Cells under Treg conditions had an up-regulated FOXP3 gene and a down-regulated RAR-related orphan receptor C (RORC) gene. Cells derived from the Th17 condition exhibited a down-regulated FOXP3 gene and had significantly higher RORC gene expression than Treg cells. Both resulting cells showed intracellular production of IL-17A and IL-10. Th17 condition-cultured cells exhibited more glycolytic activity and glucose uptake compared to the Treg cells. The findings suggest that cells obtained from established protocols for the differentiation of iTreg and Th17 cells in vitro are possibly in the intermediate stage of differentiation or may be two different types of cells that share a lineage-specific differentiation program.
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Affiliation(s)
- Jarupa Soongsathitanon
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Ticha Homjan
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Suthatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok, 65000, Thailand
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6
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Kröger B, Spohn M, Mengel M, Sperhake JP, Ondruschka B, Mailer RK. Expression of full-length FOXP3 exceeds other isoforms in thymus and stimulated CD4 + T cells. J Clin Immunol 2024; 44:114. [PMID: 38676826 PMCID: PMC11055749 DOI: 10.1007/s10875-024-01715-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/19/2024] [Indexed: 04/29/2024]
Affiliation(s)
- Benita Kröger
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Spohn
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marion Mengel
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan-Peter Sperhake
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benjamin Ondruschka
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Reiner K Mailer
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Zou Z, Cheng Q, Zhou J, Guo C, Hadjinicolaou AV, Salio M, Liang X, Yang C, Du Y, Yao W, Wang D, Cerundolo V, Wang Q, Xia M. ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4 + T cells in low arginine condition. Cell Rep 2024; 43:113995. [PMID: 38527061 DOI: 10.1016/j.celrep.2024.113995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/21/2024] [Accepted: 03/08/2024] [Indexed: 03/27/2024] Open
Abstract
The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.
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Affiliation(s)
- Ziqi Zou
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qian Cheng
- MRC Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, UK
| | - Jiajie Zhou
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Chenyao Guo
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Andreas V Hadjinicolaou
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, UK; Early Cancer Institute, Department of Oncology, Hutchison Research Centre, University of Cambridge, CB2 0XZ Cambridge, UK
| | - Mariolina Salio
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, UK
| | - Xinghua Liang
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China
| | - Cuiyu Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yue Du
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Weiran Yao
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Dongrui Wang
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China
| | - Vincenzo Cerundolo
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, UK
| | - Qingqing Wang
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China.
| | - Meng Xia
- Institute of Immunology, and Department of Dermatology and Venereology of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, UK.
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8
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Saleh QW, Mohammadnejad A, Tepel M. FOXP3 full length splice variant is associated with kidney allograft tolerance. Front Immunol 2024; 15:1389105. [PMID: 38660296 PMCID: PMC11040551 DOI: 10.3389/fimmu.2024.1389105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 03/29/2024] [Indexed: 04/26/2024] Open
Abstract
Background Progressive decline of allograft function leads to premature graft loss. Forkhead box P3 (FOXP3), a characteristic gene of T-regulatory cells, is known to be essential for auto-antigen tolerance. We assessed the hypothesis that low FOXP3 mRNA splice variant levels in peripheral blood cells early after transplantation are associated with progressive allograft injury. Methods Blood samples were prospectively collected from 333 incident kidney transplant recipients on the first and 29th postoperative day. We used quantitative polymerase chain reaction to determine transcripts of 3 isotypes of FOXP3 splice variants, including pre-mature FOXP3 and full length FOXP3 (FOXP3fl). We investigated the association between FOXP3 splice variant levels and the declines in estimated glomerular filtration rate (eGFR) of more than 5ml/min/1.73m2 within the first-year post-transplant using logistic regression. Results We observed lower FOXP3fl levels in recipients with declining eGFR (N = 132) than in recipients with stable eGFR (N = 201), (logarithmic value -4.13 [IQR -4.50 to -3.84] vs -4.00 [4.32 to -3.74], p=0.02). In ad hoc analysis pre-transplant FOXP3fl levels were similar in both groups. The association between FOXP3fl and declining eGFR was confirmed by multivariable analysis adjusted for potential confounding factors (Odds Ratio 0.51, 95% confidence interval 0.28 to 0.91: p=0.02). When stratifying FOXP3fl levels into quartiles, recipients with lower day1 FOXP3fl had the highest rate of declining eGFR (p=0.04). Conclusion Low FOXP3fl splice variant levels at the first postoperative day in kidney transplant recipients were associated with severe decline of eGFR, a well-known surrogate for hard endpoints.
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Affiliation(s)
- Qais W. Saleh
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Cardiovascular and Renal Research, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Afsaneh Mohammadnejad
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark
| | - Martin Tepel
- Department of Nephrology, Odense University Hospital, Odense, Denmark
- Cardiovascular and Renal Research, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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9
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Zhang YS, Chen YQ. Dysfunctional regulatory T cell: May be an obstacle to immunotherapy in cardiovascular diseases. Biomed Pharmacother 2024; 173:116359. [PMID: 38430633 DOI: 10.1016/j.biopha.2024.116359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/18/2024] [Accepted: 02/26/2024] [Indexed: 03/05/2024] Open
Abstract
Inflammatory responses are linked to cardiovascular diseases (CVDs) in various forms. Tregs, members of CD4+ T cells, play important roles in regulating immune system and suppressing inflammatory response, thus contributing to maintaining immune homeostasis. However, Tregs exert their powerful suppressive function relying on the stable phenotype and function. The stability of Tregs primarily depends on the FOXP3 (Forkhead box P3) expression and epigenetic regulation. Although Tregs are quite stable under physiological conditions, prolonged exposure to inflammatory cues, Tregs may lose suppressive function and require proinflammatory phenotype, namely plastic Tregs or ex-Tregs. There are extensive researches have established the beneficial role of Tregs in CVDs. Nevertheless, the potential risks of dysfunctional Tregs lack deep research. Anti-inflammatory and immunological modulation have been hotspots in the treatment of CVDs. Tregs are appealing because of their crucial role in resolving inflammation and promoting tissue repair. If alleviating inflammatory response through modulating Tregs could be a new therapeutic strategy for CVDs, the next step to consider is how to prevent the formation of dysfunctional Tregs or reverse detrimental Tregs to normal phenotype.
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Affiliation(s)
- Yu-Sha Zhang
- Department of Cardiology, the Second Xiangya Hospital, Central South University, Hunan, China
| | - Ya-Qin Chen
- Department of Cardiology, the Second Xiangya Hospital, Central South University, Hunan, China.
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10
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Baudouin R, Hans S, Lisan Q, Morin B, Adimi Y, Martin J, Lechien JR, Tartour E, Badoual C. Prognostic Significance of the Microenvironment in Human Papillomavirus Oropharyngeal Carcinoma: A Systematic Review. Laryngoscope 2024; 134:1507-1516. [PMID: 37642393 DOI: 10.1002/lary.31010] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/01/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023]
Abstract
OBJECTIVE The immune microenvironment of HPV-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) (HPV+OPSCCs) differs from that of HPV-independent oropharyngeal cancers (HPV-independent OPSCCs). The literature on the subject is very abundant, demanding an organized synthesis of this wealth of information to evaluate the hypothesis associating the favorable prognosis of HPV+OPSCC patients with a different immune microenvironment. A systematic review of the literature was conducted regarding the microenvironment of HPV+OPSCCs. DATA SOURCE MEDLINE/PubMed, Embase, and Cochrane Library databases. REVIEW METHODS A literature search was performed following PRISMA guidelines (Moher D. PLoS Med. 2009). The PEO (Population, Exposure, and Outcome) framework is detailed as follows: P: patients with oropharyngeal squamous cell carcinomas, E: human papillomavirus (HPV), and O: histological and immunological composition of the tumoral microenvironment (TME). No meta-analysis was performed. RESULTS From 1,202 studies that were screened, 58 studies were included (n = 6,474 patients; n = 3,581 (55%) HPV+OPSCCs and n = 2,861(45%) HPV-independent OPSCCs). The presence of tumor-infiltrating lymphocytes (TIL), CD3+ in 1,733 patients, CD4+ in 520 patients, and CD8+ (cytotoxic T lymphocytes (CTL)) in 3,104 patients, and high levels of PD-L1 expression in 1,222 patients is strongly correlated with an improved clinical outcome in HPV+OPSCCs. CONCLUSION This systematic review provides the most comprehensive information on the immune microenvironment of HPV+OPSCCs to date. Tumor-infiltrating lymphocytes and PD-L1 expression are associated with a favorable prognosis. B, CD8+ and resident memory cells densities are higher in HPV+OPSCCs. The importance of myeloid lineages is still a matter of debate and research. LEVEL OF EVIDENCE NA Laryngoscope, 134:1507-1516, 2024.
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Affiliation(s)
- R Baudouin
- Department of Otolaryngology-Head & Neck Surgery, Foch Hospital, Suresnes, France
- School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Montigny-le-Bretonneux, France
| | - S Hans
- Department of Otolaryngology-Head & Neck Surgery, Foch Hospital, Suresnes, France
- School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Montigny-le-Bretonneux, France
| | - Q Lisan
- Department of Otolaryngology-Head & Neck Surgery, Foch Hospital, Suresnes, France
- School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Montigny-le-Bretonneux, France
| | - B Morin
- Department of Pathology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
| | - Y Adimi
- Department of Pathology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
| | - J Martin
- Department of Pathology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
| | - J R Lechien
- Department of Otolaryngology-Head & Neck Surgery, Foch Hospital, Suresnes, France
- School of Medicine, UFR Simone Veil, Université Versailles Saint-Quentin-en-Yvelines (Paris Saclay University), Montigny-le-Bretonneux, France
| | - E Tartour
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
| | - C Badoual
- Department of Pathology, Hôpital Européen Georges Pompidou, Université Paris Cité, INSERM, PARCC, Paris, France
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11
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Chen H, Wang X, Wang Y, Chang X. What happens to regulatory T cells in multiple myeloma. Cell Death Discov 2023; 9:468. [PMID: 38129374 PMCID: PMC10739837 DOI: 10.1038/s41420-023-01765-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
Abnormal tumor microenvironment and immune escape in multiple myeloma (MM) are associated with regulatory T cells (Tregs), which play an important role in maintaining self-tolerance and regulating the overall immune response to infection or tumor cells. In patients with MM, there are abnormalities in the number, function and distribution of Tregs, and these abnormalities may be related to the disease stage, risk grade and prognosis of patients. During the treatment, Tregs have different responses to various treatment regiments, thus affecting the therapeutic effect of MM. It is also possible to predict the therapeutic response by observing the changes of Tregs. In addition to the above, we reviewed the application of Tregs in the treatment of MM. In conclusion, there is still much room for research on the mechanism and application of Tregs in MM.
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Affiliation(s)
- Huixian Chen
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Xueling Wang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Yan Wang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xiaotian Chang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
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12
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Biswas M, So K, Bertolini TB, Krishnan P, Rana J, Muñoz-Melero M, Syed F, Kumar SRP, Gao H, Xuei X, Terhorst C, Daniell H, Cao S, Herzog RW. Distinct functions and transcriptional signatures in orally induced regulatory T cell populations. Front Immunol 2023; 14:1278184. [PMID: 37954612 PMCID: PMC10637621 DOI: 10.3389/fimmu.2023.1278184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Oral administration of antigen induces regulatory T cells (Treg) that can not only control local immune responses in the small intestine, but also traffic to the central immune system to deliver systemic suppression. Employing murine models of the inherited bleeding disorder hemophilia, we find that oral antigen administration induces three CD4+ Treg subsets, namely FoxP3+LAP-, FoxP3+LAP+, and FoxP3-LAP+. These T cells act in concert to suppress systemic antibody production induced by therapeutic protein administration. Whilst both FoxP3+LAP+ and FoxP3-LAP+ CD4+ T cells express membrane-bound TGF-β (latency associated peptide, LAP), phenotypic, functional, and single cell transcriptomic analyses reveal distinct characteristics in the two subsets. As judged by an increase in IL-2Rα and TCR signaling, elevated expression of co-inhibitory receptor molecules and upregulation of the TGFβ and IL-10 signaling pathways, FoxP3+LAP+ cells are an activated form of FoxP3+LAP- Treg. Whereas FoxP3-LAP+ cells express low levels of genes involved in TCR signaling or co-stimulation, engagement of the AP-1 complex members Jun/Fos and Atf3 is most prominent, consistent with potent IL-10 production. Single cell transcriptomic analysis further reveals that engagement of the Jun/Fos transcription factors is requisite for mediating TGFβ expression. This can occur via an Il2ra dependent or independent process in FoxP3+LAP+ or FoxP3-LAP+ cells respectively. Surprisingly, both FoxP3+LAP+ and FoxP3-LAP+ cells potently suppress and induce FoxP3 expression in CD4+ conventional T cells. In this process, FoxP3-LAP+ cells may themselves convert to FoxP3+ Treg. We conclude that orally induced suppression is dependent on multiple regulatory cell types with complementary and interconnected roles.
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Affiliation(s)
- Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kaman So
- Department of Biostatistics and Health Data Science and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Thais B. Bertolini
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Preethi Krishnan
- Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Jyoti Rana
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Maite Muñoz-Melero
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Farooq Syed
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sandeep R. P. Kumar
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Hongyu Gao
- Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Xiaoling Xuei
- Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, United States
| | - Henry Daniell
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Sha Cao
- Department of Biostatistics and Health Data Science and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Roland W. Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
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13
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Bakhtiyari M, Liaghat M, Aziziyan F, Shapourian H, Yahyazadeh S, Alipour M, Shahveh S, Maleki-Sheikhabadi F, Halimi H, Forghaniesfidvajani R, Zalpoor H, Nabi-Afjadi M, Pornour M. The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways. Cell Commun Signal 2023; 21:252. [PMID: 37735675 PMCID: PMC10512514 DOI: 10.1186/s12964-023-01282-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/17/2023] [Indexed: 09/23/2023] Open
Abstract
Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.
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Affiliation(s)
- Maryam Bakhtiyari
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mahsa Liaghat
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| | - Fatemeh Aziziyan
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hooriyeh Shapourian
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sheida Yahyazadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maedeh Alipour
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Shaghayegh Shahveh
- American Association of Naturopath Physician (AANP), Washington, DC, USA
| | - Fahimeh Maleki-Sheikhabadi
- Department of Hematology and Blood Banking, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Halimi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Razieh Forghaniesfidvajani
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Majid Pornour
- Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA.
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14
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Georgoulis V, Papoudou-Bai A, Makis A, Kanavaros P, Hatzimichael E. Unraveling the Immune Microenvironment in Classic Hodgkin Lymphoma: Prognostic and Therapeutic Implications. BIOLOGY 2023; 12:862. [PMID: 37372147 PMCID: PMC10294989 DOI: 10.3390/biology12060862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed-Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T cells (CD4 helper, CD8 cytotoxic and regulatory) and tumor-associated macrophages (TAMs), but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through the production of various cytokines and/or the aberrant expression of immune checkpoint molecules in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis, as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.
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Affiliation(s)
- Vasileios Georgoulis
- Department of Hematology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
| | - Alexandra Papoudou-Bai
- Department of Pathology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
| | - Alexandros Makis
- Department of Child Health, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 000 Ioannina, Greece;
| | - Eleftheria Hatzimichael
- Department of Hematology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
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15
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D’Silva SZ, Singh M, Pinto AS. NK cell defects: implication in acute myeloid leukemia. Front Immunol 2023; 14:1112059. [PMID: 37228595 PMCID: PMC10203541 DOI: 10.3389/fimmu.2023.1112059] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
Acute Myeloid Leukemia (AML) is a complex disease with rapid progression and poor/unsatisfactory outcomes. In the past few years, the focus has been on developing newer therapies for AML; however, relapse remains a significant problem. Natural Killer cells have strong anti-tumor potential against AML. This NK-mediated cytotoxicity is often restricted by cellular defects caused by disease-associated mechanisms, which can lead to disease progression. A stark feature of AML is the low/no expression of the cognate HLA ligands for the activating KIR receptors, due to which these tumor cells evade NK-mediated lysis. Recently, different Natural Killer cell therapies have been implicated in treating AML, such as the adoptive NK cell transfer, Chimeric antigen receptor-modified NK (CAR-NK) cell therapy, antibodies, cytokine, and drug treatment. However, the data available is scarce, and the outcomes vary between different transplant settings and different types of leukemia. Moreover, remission achieved by some of these therapies is only for a short time. In this mini-review, we will discuss the role of NK cell defects in AML progression, particularly the expression of different cell surface markers, the available NK cell therapies, and the results from various preclinical and clinical trials.
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Affiliation(s)
- Selma Z. D’Silva
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Meenakshi Singh
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Andrea S. Pinto
- Transplant Immunology and Immunogenetics Lab, Advanced Centre for Treatment, Education and Research in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
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16
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Nickle RA, DeOca KB, Garcia BL, Mannie MD. Soluble CD25 imposes a low-zone IL-2 signaling environment that favors competitive outgrowth of antigen-experienced CD25 high regulatory and memory T cells. Cell Immunol 2023; 384:104664. [PMID: 36642016 PMCID: PMC10257407 DOI: 10.1016/j.cellimm.2023.104664] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/13/2022] [Accepted: 01/03/2023] [Indexed: 01/07/2023]
Abstract
This study focused on soluble (s)CD25-mediated regulation of IL-2 signaling in murine and human CD4+ T cells. Recombinant sCD25 reversibly sequestered IL-2 to limit acute maximal proliferative responses while preserving IL-2 bioavailability to subsequently maintain low-zone IL-2 signaling during prolonged culture. By inhibiting IL-2 signaling during acute activation, sCD25 suppressed T-cell growth and inhibited IL-2-evoked transmembrane CD25 expression, thereby resulting in lower prevalence of CD25high T cells. By inhibiting IL-2 signaling during quiescent IL-2-mediated growth, sCD25 competed with transmembrane CD25, IL2Rβγ, and IL2Rαβγ receptors for limited pools of IL-2 such that sCD25 exhibited strong or weak inhibitory efficacy in IL-2-stimulated cultures of CD25low or CD25high T cells, respectively. Preferential blocking of IL-2 signaling in CD25low but not CD25high T cells caused competitive enrichment of CD25high memory/effector and regulatory FOXP3+ subsets. In conclusion, sCD25 modulates IL-2 bioavailability to limit CD25 expression during acute activation while enhancing CD25highT-cell dominance during low-zone homeostatic IL-2-mediated expansion, thereby 'flattening' the inflammatory curve over time.
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Affiliation(s)
- Rebecca A Nickle
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Kayla B DeOca
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Brandon L Garcia
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Mark D Mannie
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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17
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Ménoret S, Tesson L, Remy S, Gourain V, Sérazin C, Usal C, Guiffes A, Chenouard V, Ouisse LH, Gantier M, Heslan JM, Fourgeux C, Poschmann J, Guillonneau C, Anegon I. CD4 + and CD8 + regulatory T cell characterization in the rat using a unique transgenic Foxp3-EGFP model. BMC Biol 2023; 21:8. [PMID: 36635667 PMCID: PMC9837914 DOI: 10.1186/s12915-022-01502-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 12/16/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Regulatory T cells (Treg) in diverse species include CD4+ and CD8+ T cells. In all species, CD8+ Treg have been only partially characterized and there is no rat model in which CD4+ and CD8+ FOXP3+ Treg are genetically tagged. RESULTS We generated a Foxp3-EGFP rat transgenic line in which FOXP3 gene was expressed and controlled EGFP. CD4+ and CD8+ T cells were the only cells that expressed EGFP, in similar proportion as observed with anti-FOXP3 antibodies and co-labeled in the same cells. CD4+EGFP+ Treg were 5-10 times more frequent than CD8+EGFP+ Treg. The suppressive activity of CD4+ and CD8+ Treg was largely confined to EGFP+ cells. RNAseq analyses showed similarities but also differences among CD4+ and CD8+ EGFP+ cells and provided the first description of the natural FOXP3+CD8+ Treg transcriptome. In vitro culture of CD4+ and CD8+ EGFP- cells with TGFbeta and IL-2 generated induced EGFP+ Treg. CD4+ and CD8+ EGFP+ Treg were expanded upon in vivo administration of a low dose of IL-2. CONCLUSIONS This new and unique rat line constitutes a useful model to identify and isolate viable CD4+ and CD8+ FOXP3+ Treg. Additionally, it allows to identify molecules expressed in CD8+ Treg that may allow to better define their phenotype and function not only in rats but also in other species.
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Affiliation(s)
- Séverine Ménoret
- grid.277151.70000 0004 0472 0371Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016 CNRS UMS 3556, F-44000 Nantes, France ,grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Laurent Tesson
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Séverine Remy
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Victor Gourain
- grid.277151.70000 0004 0472 0371Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016 CNRS UMS 3556, F-44000 Nantes, France
| | - Céline Sérazin
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Claire Usal
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Aude Guiffes
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Vanessa Chenouard
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Laure-Hélène Ouisse
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Malika Gantier
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Jean-Marie Heslan
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Cynthia Fourgeux
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Jeremie Poschmann
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Carole Guillonneau
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
| | - Ignacio Anegon
- grid.4817.a0000 0001 2189 0784INSERM, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, Nantes, France
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18
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Bojanic I, Worel N, Pacini CP, Stary G, Piekarska A, Flinn AM, Schell KJ, Gennery AR, Knobler R, Lacerda JF, Greinix HT, Pulanic D, Crossland RE. Extracorporeal photopheresis as an immunomodulatory treatment modality for chronic GvHD and the importance of emerging biomarkers. Front Immunol 2023; 14:1086006. [PMID: 36875063 PMCID: PMC9981637 DOI: 10.3389/fimmu.2023.1086006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/01/2023] [Indexed: 02/19/2023] Open
Abstract
Haematopoietic stem cell transplantation (HSCT) is the treatment of choice for malignant haematological diseases. Despite continuous improvements in pre- and post-transplantation procedures, the applicability of allo-HSCT is limited by life-threatening complications such as graft-versus-host disease (GvHD), engraftment failure, and opportunistic infections. Extracorporeal photopheresis (ECP) is used to treat steroid resistant GvHD with significant success. However, the molecular mechanisms driving its immunomodulatory action, whilst preserving immune function, require further understanding. As ECP is safe to administer with few significant adverse effects, it has the potential for earlier use in the post-HSCT treatment of GvHD. Thus, further understanding the immunomodulatory mechanisms of ECP action may justify more timely use in clinical practice, as well as identify biomarkers for using ECP as first line or pre-emptive GvHD therapy. This review aims to discuss technical aspects and response to ECP, review ECP as an immunomodulatory treatment modality for chronic GvHD including the effect on regulatory T cells and circulating vs. tissue-resident immune cells and consider the importance of emerging biomarkers for ECP response.
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Affiliation(s)
- Ines Bojanic
- Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, Zagreb, Croatia.,School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nina Worel
- Department of Transfusion Medicine and Cell Therapy, Medical University of Vienna, Vienna, Austria
| | - Carolina P Pacini
- Hematology and Transplantation Immunology, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna, Austria.,CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.,Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
| | - Agnieszka Piekarska
- Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Aisling M Flinn
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Kimberly J Schell
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Andrew R Gennery
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.,Paediatric Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
| | - Robert Knobler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - João F Lacerda
- Hematology and Transplantation Immunology, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | | | - Drazen Pulanic
- School of Medicine, University of Zagreb, Zagreb, Croatia.,Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Rachel E Crossland
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
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19
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Sanders JM, Jeyamogan S, Mathew JM, Leventhal JR. Foxp3+ regulatory T cell therapy for tolerance in autoimmunity and solid organ transplantation. Front Immunol 2022; 13:1055466. [PMID: 36466912 PMCID: PMC9714335 DOI: 10.3389/fimmu.2022.1055466] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/02/2022] [Indexed: 08/03/2023] Open
Abstract
Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.
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Affiliation(s)
- Jes M. Sanders
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Shareni Jeyamogan
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - James M. Mathew
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Joseph R. Leventhal
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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20
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Mohd Idris RA, Mussa A, Ahmad S, Al-Hatamleh MAI, Hassan R, Tengku Din TADAA, Wan Abdul Rahman WF, Lazim NM, Boer JC, Plebanski M, Mohamud R. The Effects of Tamoxifen on Tolerogenic Cells in Cancer. BIOLOGY 2022; 11:1225. [PMID: 36009853 PMCID: PMC9405160 DOI: 10.3390/biology11081225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 11/30/2022]
Abstract
Tamoxifen (TAM) is the most prescribed selective estrogen receptor modulator (SERM) to treat hormone-receptor-positive breast cancer patients and has been used for more than 20 years. Its role as a hormone therapy is well established; however, the potential role in modulating tolerogenic cells needs to be better clarified. Infiltrating tumor-microenvironment-regulatory T cells (TME-Tregs) are important as they serve a suppressive function through the transcription factor Forkhead box P3 (Foxp3). Abundant studies have suggested that Foxp3 regulates the expression of several genes (CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, TNFR2) involved in carcinogenesis to utilize its tumor suppressor function through knockout models. TAM is indirectly concomitant via the Cre/loxP system by allowing nuclear translocation of the fusion protein, excision of the floxed STOP cassette and heritable expression of encoding fluorescent protein in a cohort of cells that express Foxp3. Moreover, TAM administration in breast cancer treatment has shown its effects directly through MDSCs by the enrichment of its leukocyte populations, such as NK and NKT cells, while it impairs the differentiation and activation of DCs. However, the fundamental mechanisms of the reduction of this pool by TAM are unknown. Here, we review the vital effects of TAM on Tregs for a precise mechanistic understanding of cancer immunotherapies.
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Affiliation(s)
- Ros Akmal Mohd Idris
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Ali Mussa
- Haematology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
- Department of Biology, Faculty of Education, Omdurman Islamic University, Omdurman P.O. Box 382, Sudan
| | - Suhana Ahmad
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Mohammad A. I. Al-Hatamleh
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Rosline Hassan
- Haematology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | | | - Wan Faiziah Wan Abdul Rahman
- Pathology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Norhafiza Mat Lazim
- Otorhinolaryngology Department-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Jennifer C. Boer
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Magdalena Plebanski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Rohimah Mohamud
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
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21
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Tian X, Ning Q, Yu J, Tang S. T-cell immunoglobulin and ITIM domain in cancer immunotherapy: A focus on tumor-infiltrating regulatory T cells. Mol Immunol 2022; 147:62-70. [DOI: 10.1016/j.molimm.2022.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/06/2022] [Accepted: 04/24/2022] [Indexed: 12/17/2022]
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22
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Hino C, Pham B, Park D, Yang C, Nguyen MH, Kaur S, Reeves ME, Xu Y, Nishino K, Pu L, Kwon SM, Zhong JF, Zhang KK, Xie L, Chong EG, Chen CS, Nguyen V, Castillo DR, Cao H. Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products. Biomedicines 2022; 10:biomedicines10061410. [PMID: 35740430 PMCID: PMC9219790 DOI: 10.3390/biomedicines10061410] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) plays an essential role in the development, proliferation, and survival of leukemic blasts in acute myeloid leukemia (AML). Within the bone marrow and peripheral blood, various phenotypically and functionally altered cells in the TME provide critical signals to suppress the anti-tumor immune response, allowing tumor cells to evade elimination. Thus, unraveling the complex interplay between AML and its microenvironment may have important clinical implications and are essential to directing the development of novel targeted therapies. This review summarizes recent advancements in our understanding of the AML TME and its ramifications on current immunotherapeutic strategies. We further review the role of natural products in modulating the TME to enhance response to immunotherapy.
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Affiliation(s)
- Christopher Hino
- Department of Internal Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (C.H.); (B.P.); (K.N.); (L.P.); (S.M.K.)
| | - Bryan Pham
- Department of Internal Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (C.H.); (B.P.); (K.N.); (L.P.); (S.M.K.)
| | - Daniel Park
- Department of Internal Medicine, School of Medicine, University of California San Francisco–Fresno, Fresno, CA 93701, USA;
| | - Chieh Yang
- Department of Internal Medicine, School of Medicine, University of California Riverside, Riverside, CA 92521, USA;
| | - Michael H.K. Nguyen
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
| | - Simmer Kaur
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
| | - Mark E. Reeves
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
| | - Yi Xu
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
| | - Kevin Nishino
- Department of Internal Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (C.H.); (B.P.); (K.N.); (L.P.); (S.M.K.)
| | - Lu Pu
- Department of Internal Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (C.H.); (B.P.); (K.N.); (L.P.); (S.M.K.)
| | - Sue Min Kwon
- Department of Internal Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (C.H.); (B.P.); (K.N.); (L.P.); (S.M.K.)
| | - Jiang F. Zhong
- Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA;
| | - Ke K. Zhang
- Department of Nutrition, Texas A&M University, College Station, TX 77030, USA; (K.K.Z.); (L.X.)
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX 77030, USA; (K.K.Z.); (L.X.)
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA
| | - Esther G. Chong
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
| | - Chien-Shing Chen
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
| | - Vinh Nguyen
- Department of Biology, University of California Riverside, Riverside, CA 92521, USA;
| | - Dan Ran Castillo
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
- Correspondence: (D.R.C.); (H.C.)
| | - Huynh Cao
- Department of Oncology/Hematology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA; (M.H.K.N.); (S.K.); (M.E.R.); (Y.X.); (E.G.C.); (C.-S.C.)
- Correspondence: (D.R.C.); (H.C.)
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23
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Jiang Z, Zhu H, Wang P, Que W, Zhong L, Li X, Du F. Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity. MedComm (Beijing) 2022; 3:e137. [PMID: 35474948 PMCID: PMC9023873 DOI: 10.1002/mco2.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022] Open
Abstract
CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery The Affiliated Hospital of Guizhou Medical University Guizhou P. R. China
| | - Pusen Wang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Weitao Que
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Lin Zhong
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Xiao‐Kang Li
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
- Division of Transplantation Immunology National Research Institute for Child Health and Development Tokyo Japan
| | - Futian Du
- Department of Hepatobiliary Surgery Weifang People's Hospital Shandong P. R. China
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24
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022; 13:812774. [PMID: 35309296 PMCID: PMC8927970 DOI: 10.3389/fimmu.2022.812774] [Citation(s) in RCA: 392] [Impact Index Per Article: 130.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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25
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Mertowska P, Mertowski S, Podgajna M, Grywalska E. The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies. J Clin Med 2022; 11:947. [PMID: 35207219 PMCID: PMC8874698 DOI: 10.3390/jcm11040947] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/29/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023] Open
Abstract
Transcription factors are an extremely important group of proteins that are responsible for the process of selective activation or deactivation of other cellular proteins, usually at the last stage of signal transmission in the cell. An important family of transcription factors that regulate the body's response is the FOX family which plays an important role in regulating the expression of genes involved in cell growth, proliferation, and differentiation. The members of this family include the intracellular protein Foxp3, which regulates the process of differentiation of the T lymphocyte subpopulation, and more precisely, is responsible for the development of regulatory T lymphocytes. This protein influences several cellular processes both directly and indirectly. In the process of cytokine production regulation, the Foxp3 protein interacts with numerous proteins and transcription factors such as NFAT, nuclear factor kappa B, and Runx1/AML1 and is involved in the process of histone acetylation in condensed chromatin. Malfunctioning of transcription factor Foxp3 caused by the mutagenesis process affects the development of disorders of the immune response and autoimmune diseases. This applies to the impairment or inability of the immune system to fight infections due to a disruption of the mechanisms supporting immune homeostasis which in turn leads to the development of a special group of disorders called primary immunodeficiencies (PID). The aim of this review is to provide information on the role of the Foxp3 protein in the human body and its involvement in the development of two types of primary immunodeficiency diseases: IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome) and CVID (Common Variable Immunodeficiency).
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Affiliation(s)
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland; (P.M.); (M.P.); (E.G.)
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26
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Younes SA. Mitochondrial Exhaustion of Memory CD4 T-Cells in Treated HIV-1 Infection. IMMUNOMETABOLISM 2022; 4:e220013. [PMID: 35633761 PMCID: PMC9140223 DOI: 10.20900/immunometab20220013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
People living with HIV (PLWH) who are immune non-responders (INR) to therapy are unable to restore their CD4 T-cell count and remain at great risk of morbidity and mortality. Here the mitochondrial defects that characterize memory CD4 T-cells in INR and causes of this mitochondrial exhaustion are reviewed. This review also describes the various reagents used to induce the expression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis, which can restore mitochondria fitness and CD4 T-cell proliferation in INR. Due to sustained heightened inflammation in INR, the mitochondrial network is unable to be rejuvenated and requires attenuation of mediators of inflammation to rescue mitochondria and CD4 T-cell counts in INR.
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Affiliation(s)
- Souheil-Antoine Younes
- Department of Pathology, Pathology Advanced Translational Research (PATRU), School of Medicine, Emory University, Atlanta 30322, USA
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27
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Sahebnasagh A, Saghafi F, Negintaji S, Hu T, Shabani-Borujeni M, Safdari M, Ghaleno HR, Miao L, Qi Y, Wang M, Liao P, Sureda A, Simal-Gándara J, Nabavi SM, Xiao J. Nitric Oxide and Immune Responses in Cancer: Searching for New Therapeutic Strategies. Curr Med Chem 2022; 29:1561-1595. [PMID: 34238142 DOI: 10.2174/0929867328666210707194543] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/05/2021] [Accepted: 05/15/2021] [Indexed: 02/08/2023]
Abstract
In recent years, there has been an increasing interest in understanding the mysterious functions of nitric oxide (NO) and how this pleiotropic signaling molecule contributes to tumorigenesis. This review attempts to expose and discuss the information available on the immunomodulatory role of NO in cancer and recent approaches to the role of NO donors in the area of immunotherapy. To address the goal, the following databases were searched to identify relevant literature concerning empirical evidence: The Cochrane Library, Pubmed, Medline, and EMBASE from 1980 through March 2020. Valuable attempts have been made to develop distinctive NO-based cancer therapy. Although the data do not allow generalization, the evidence seems to indicate that low/moderate levels may favor tumorigenesis, while higher levels would exert antitumor effects. In this sense, the use of NO donors could have an important therapeutic potential within immunotherapy, although there are still no clinical trials. The emerging understanding of NO-regulated immune responses in cancer may help unravel the recent features of this "doubleedged sword" in cancer physiological and pathologic processes and its potential use as a therapeutic agent for cancer treatment. In short, in this review, we discuss the complex cellular mechanism in which NO, as a pleiotropic signaling molecule, participates in cancer pathophysiology. We also debate the dual role of NO in cancer and tumor progression and clinical approaches for inducible nitric oxide synthase (iNOS) based therapy against cancer.
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Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sina Negintaji
- Student Research Committee, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Tingyan Hu
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Mojtaba Shabani-Borujeni
- Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Safdari
- Department of Orthopedic Surgery, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Hassan Rezai Ghaleno
- Department of Surgery, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Lingchao Miao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao
| | - Yaping Qi
- Purdue Quantum Science and Engineering Institute, Purdue University, West Lafayette, IN 47907, USA
| | - Mingfu Wang
- School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Pan Liao
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, and Balearic Islands Health Research Institute (IdISBa), University of the Balearic Islands, Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Jesus Simal-Gándara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
- International Research Centre for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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Tettamanti S, Pievani A, Biondi A, Dotti G, Serafini M. Catch me if you can: how AML and its niche escape immunotherapy. Leukemia 2022; 36:13-22. [PMID: 34302116 PMCID: PMC8727297 DOI: 10.1038/s41375-021-01350-x] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.
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Affiliation(s)
- Sarah Tettamanti
- Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy
| | - Alice Pievani
- Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy
| | - Andrea Biondi
- Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy.
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Marta Serafini
- Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy
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Halloran PF, Einecke G, Sikosana MLN, Madill-Thomsen K. The Biology and Molecular Basis of Organ Transplant Rejection. Handb Exp Pharmacol 2022; 272:1-26. [PMID: 35091823 DOI: 10.1007/164_2021_557] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Allograft rejection is defined as tissue injury in a transplanted allogeneic organ produced by the effector mechanisms of the adaptive alloimmune response. Effector T lymphocytes and IgG alloantibodies cause two different types of rejection that can occur either individually or simultaneously: T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). In TCMR, cognate effector T cells infiltrate the graft and orchestrate an interstitial inflammatory response in the kidney interstitium in which effector T cells engage antigen-presenting myeloid cells, activating the T cells, antigen-presenting cells, and macrophages. The result is intense expression of IFNG and IFNG-induced molecules, expression of effector T cell molecules and macrophage molecules and checkpoints, and deterioration of parenchymal function. The diagnostic lesions of TCMR follow, i.e. interstitial inflammation, parenchymal deterioration, and intimal arteritis. In ABMR, HLA IgG alloantibodies produced by plasma cells bind to the donor antigens on graft microcirculation, leading to complement activation, margination, and activation of NK cells and neutrophils and monocytes, and endothelial injury, sometimes with intimal arteritis. TCMR becomes infrequent after 5-10 years post-transplant, probably reflecting adaptive mechanisms such as checkpoints, but ABMR can present even decades post-transplant. Some rejection is triggered by inadequate immunosuppression and non-adherence, challenging the clinician to target effective immunosuppression even decades post-transplant.
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Affiliation(s)
- Philip F Halloran
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
| | - Gunilla Einecke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Majid L N Sikosana
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Inoue CJ, Flauzino T, Gonçalves BP, Paula JCCD, Galvão TC, Miyazaki PK, Alcantara CCD, Westmore LRES, Lozovoy MAB, Reiche EMV, Simão ANC. FOXP3 variants are independently associated with transforming growth factor Β1 plasma levels in female patients with inflammatory bowel disease. Clinics (Sao Paulo) 2022; 77:100084. [PMID: 35905575 PMCID: PMC9335380 DOI: 10.1016/j.clinsp.2022.100084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/28/2021] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-β1 plasma levels. METHOD The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-β1 were determined using immunofluorimetric assay. RESULTS AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-β1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-β1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. CONCLUSIONS These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD.
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Affiliation(s)
- Cláudia Junko Inoue
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil; Outpatient Clinic of Gastroenterology, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Tamires Flauzino
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Beatriz Piantoni Gonçalves
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil; Outpatient Clinic of Gastroenterology, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | | | - Talita Cristina Galvão
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Paula Kikuchi Miyazaki
- Laboratory of Research in Applied Immunology, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | | | | | - Marcell Alysson Batisti Lozovoy
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Edna Maria Vissoci Reiche
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Andréa Name Colado Simão
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Universidade Estadual de Londrina, Londrina, PR, Brazil.
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Ruhnke L, Stölzel F, Oelschlägel U, von Bonin M, Sockel K, Middeke JM, Röllig C, Jöhrens K, Schetelig J, Thiede C, Bornhäuser M. Long-Term Mixed Chimerism After Ex Vivo/In Vivo T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation in Patients With Myeloid Neoplasms. Front Oncol 2021; 11:776946. [PMID: 34950586 PMCID: PMC8688843 DOI: 10.3389/fonc.2021.776946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/08/2021] [Indexed: 01/06/2023] Open
Abstract
In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4+/CD34+ short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC <95% at ≥12 months post-HCT). Median follow-up was 11 years. All patients had received combined ex vivo/in vivo T cell-depleted (TCD) peripheral blood stem cells; none experienced ≥grade 2 acute graft-versus-host disease (GVHD). The mean total PBMC, CD4+, and CD34+ DC of all patients were 95.88%, 85.84%, and 90.15%, respectively. Reduced-intensity conditioning (RIC) was associated with a trend to lower mean total DC. Of note, two patients who experienced relapse had lower CD34+ DC but higher CD4+ DC as compared with patients in continuous remission. Bone marrow evaluation revealed increased CD4+/FOXP3+ cells in patients with MC, which might indicate expansion of regulatory T cells (Tregs). Our results support known predictive factors associated with MC such as RIC and TCD, promote the value of CD34+ MC as a potential predictor of relapse, highlight the potential association of CD4+ MC with reduced risk of GVHD, and indicate a possible role of Tregs in the maintenance of immune tolerance post-HCT.
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Affiliation(s)
- Leo Ruhnke
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- *Correspondence: Leo Ruhnke,
| | - Friedrich Stölzel
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
| | - Uta Oelschlägel
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Malte von Bonin
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katja Sockel
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Jan Moritz Middeke
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
| | - Christoph Röllig
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Korinna Jöhrens
- Institute of Pathology, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Johannes Schetelig
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- DKMS Clinical Trials Unit, Dresden, Germany
| | - Christian Thiede
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- AgenDix GmbH, Dresden, Germany
| | - Martin Bornhäuser
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany
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Treg/Th17 Cell Balance in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure at Different Disease Stages. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9140602. [PMID: 34869773 PMCID: PMC8641988 DOI: 10.1155/2021/9140602] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/11/2021] [Indexed: 01/12/2023]
Abstract
Background T-helper 17 (Th17) and CD4+CD25+ T-regulatory (Treg) cells play important roles in the pathogenesis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This study is aimed at investigating shifts in Treg/Th17 balance in the peripheral blood of HBV-ACLF patients at different disease stages. Methods Sixty HBV-ACLF patients, admitted to the First Hospital of Hunan University of Chinese Medicine, China, including early-stage (n = 20), middle-stage (n = 20), and late-stage patients (n = 20), were enrolled in the study. In addition, 20 patients with chronic hepatitis B and 20 healthy volunteers were also included in the study as controls. Flow cytometry, cytometric bead array, and quantitative real-time PCR protocols were used to evaluate the expression of Treg and Th17 cells as well as of related cytokines. Results The levels of Th17 cells and their effectors interleukin- (IL-) 17A, IL-23, and tumor necrosis factor-α increased with disease progression. Similarly, Treg cells and their effector cytokines transforming growth factor-β and IL-10 also increased. Although Treg and Th17 levels were positively correlated, the latter were always at higher numbers. Noteworthy, the Treg/Th17 ratio gradually decreased and was negatively correlated with ACLF severity. FoxP3 levels in the peripheral blood gradually decreased with ACLF progression, whereas ROR-γt gradually increased. Serum c-reactive protein, procalcitonin, and lipopolysaccharide were also upregulated with disease progression and positively correlated with Th17 abundance. Further, Th17, IL-17A, and IL-23 were independent risk factors for ACLF. A prognostic model for HBV-ACLF was established, with a correct prediction rate of 90.00% (54/60). Conclusion Treg/Th17 imbalance occurs throughout the pathogenic course of HBV-ACLF, with an imbalance shift toward Th17. Hence, the Th17-mediated inflammatory response drives HBV-ACLF-associated inflammation and supports the pathological mechanisms of liver failure.
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Volta V, Pérez-Baos S, de la Parra C, Katsara O, Ernlund A, Dornbaum S, Schneider RJ. A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells. Nat Commun 2021; 12:6979. [PMID: 34848685 PMCID: PMC8632918 DOI: 10.1038/s41467-021-27087-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 11/02/2021] [Indexed: 12/16/2022] Open
Abstract
Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5' noncoding regions. Silencing DAP5 in isolated human naive CD4+ T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation.
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Affiliation(s)
- Viviana Volta
- Synthis LLC, 430 East 29th Street, Launch Labs, Alexandria Center for Life Sciences, New York, NY, 10016, USA
| | - Sandra Pérez-Baos
- Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Columba de la Parra
- Department of Chemistry, Herbert H. Lehman College, City University of New York, The Graduate Center, Biochemistry Ph.D. Program, City University of New York, New York, NY, 10016, USA
| | - Olga Katsara
- Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Amanda Ernlund
- Johns Hopkins Applied Physics Lab, 11000 Johns Hopkins Road, Laurel, MD, 20723, USA
| | - Sophie Dornbaum
- Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Robert J Schneider
- Department of Microbiology, NYU Grossman School of Medicine, New York, NY, 10016, USA.
- Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, 10016, USA.
- Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY, 10016, USA.
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Cortés-Hernández A, Alvarez-Salazar EK, Arteaga-Cruz S, Rosas-Cortina K, Linares N, Alberú Gómez JM, Soldevila G. Highly Purified Alloantigen-Specific Tregs From Healthy and Chronic Kidney Disease Patients Can Be Long-Term Expanded, Maintaining a Suppressive Phenotype and Function in the Presence of Inflammatory Cytokines. Front Immunol 2021; 12:686530. [PMID: 34777330 PMCID: PMC8581357 DOI: 10.3389/fimmu.2021.686530] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 10/11/2021] [Indexed: 01/16/2023] Open
Abstract
The adoptive transfer of alloantigen-specific regulatory T cells (alloTregs) has been proposed as a therapeutic alternative in kidney transplant recipients to the use of lifelong immunosuppressive drugs that cause serious side effects. However, the clinical application of alloTregs has been limited due to their low frequency in peripheral blood and the scarce development of efficient protocols to ensure their purity, expansion, and stability. Here, we describe a new experimental protocol that allows the long-term expansion of highly purified allospecific natural Tregs (nTregs) from both healthy controls and chronic kidney disease (CKD) patients, which maintain their phenotype and suppressive function under inflammatory conditions. Firstly, we co-cultured CellTrace Violet (CTV)-labeled Tregs from CKD patients or healthy individuals with allogeneic monocyte-derived dendritic cells in the presence of interleukin 2 (IL-2) and retinoic acid. Then, proliferating CD4+CD25hiCTV− Tregs (allospecific) were sorted by fluorescence-activated cell sorting (FACS) and polyclonally expanded with anti-CD3/CD28-coated beads in the presence of transforming growth factor beta (TGF-β), IL-2, and rapamycin. After 4 weeks, alloTregs were expanded up to 2,300 times the initial numbers with a purity of >95% (CD4+CD25hiFOXP3+). The resulting allospecific Tregs showed high expressions of CTLA-4, LAG-3, and CD39, indicative of a highly suppressive phenotype. Accordingly, expanded alloTregs efficiently suppressed T-cell proliferation in an antigen-specific manner, even in the presence of inflammatory cytokines (IFN-γ, IL-4, IL-6, or TNF-α). Unexpectedly, the long-term expansion resulted in an increased methylation of the specific demethylated region of Foxp3. Interestingly, alloTregs from both normal individuals and CKD patients maintained their immunosuppressive phenotype and function after being expanded for two additional weeks under an inflammatory microenvironment. Finally, phenotypic and functional evaluation of cryopreserved alloTregs demonstrated the feasibility of long-term storage and supports the potential use of this cellular product for personalized Treg therapy in transplanted patients.
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Affiliation(s)
- Arimelek Cortés-Hernández
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Evelyn Katy Alvarez-Salazar
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Saúl Arteaga-Cruz
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Katya Rosas-Cortina
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Nadyeli Linares
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Josefina M Alberú Gómez
- National Laboratory of Flow Cytometry, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Gloria Soldevila
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Wang Z, He L, Li W, Xu C, Zhang J, Wang D, Dou K, Zhuang R, Jin B, Zhang W, Hao Q, Zhang K, Zhang W, Wang S, Gao Y, Gu J, Shang L, Tan Z, Su H, Zhang Y, Zhang C, Li M. GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma. J Immunother Cancer 2021; 9:jitc-2021-002787. [PMID: 34489334 PMCID: PMC8422483 DOI: 10.1136/jitc-2021-002787] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND A better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies. METHODS We used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15 -/-, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression. RESULTS GDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse. CONCLUSIONS Our results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.
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Affiliation(s)
- Zhaowei Wang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chuanyang Xu
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jieyu Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ran Zhuang
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Boquan Jin
- Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yuan Gao
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jintao Gu
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lei Shang
- Department of Health Statistics, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhijun Tan
- Department of Health Statistics, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Haichuan Su
- Department of oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, China
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PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity. Proc Natl Acad Sci U S A 2021; 118:2010053118. [PMID: 34312224 DOI: 10.1073/pnas.2010053118] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P 2 They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.
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Immunohistochemical Expression of FOXP3+ Regulatory T Cells in Proteinuric Primary Glomerulopathies. Int J Nephrol 2021; 2021:9961713. [PMID: 34336285 PMCID: PMC8289604 DOI: 10.1155/2021/9961713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/09/2021] [Accepted: 07/03/2021] [Indexed: 12/23/2022] Open
Abstract
FOXP3+ regulatory T-cell (Tregs) detection in renal allograft biopsies has been associated with a less intense immune response. Data about FOXP3+ Tregs' presence and role in primary glomerulopathies of native kidneys are minimal. We comparatively studied the immunohistochemical expression of FOXP3+ Tregs, CD4+ and CD3+ T cells in IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), and membranous glomerulopathy (MGN). We retrospectively reviewed 71 renal biopsies (28 from patients with IgAN, 22 from patients with FSGS and 21 from patients with MGN) performed with proteinuria as the main indication. FOXP3+ Tregs and CD4+ and CD3+ T cells in inflammatory cell infiltrates of the interstitial tissue and periglomerular space were automatically counted using image analysis software. Univariable and multivariable logistic regressions were applied for statistical analysis. Nuclear FOXP3+ immunohistochemical expression was observed in T cells in 64% of IgAN cases, 77% of FSGS cases, and 76% of MGN cases (p > 0.05). Absolute FOXP3+ Tregs count in the interstitial tissue was higher in patients without arteriolar hyalinosis than in those with arteriolar hyalinosis (1.814 ± 2.160 vs. 831 ± 696; p = 0.029). In patients with a high FOXP3+/CD4+ ratio in the interstitial tissue, the odds ratio for CKD-EPI eGFR ≥60 ml/min/1.73 m2 at biopsy was 4.80 (95% CI: 1.29-17.91; p = 0.019). FOXP3+ Tregs intrarenal infiltration in primary glomerulopathies is common. FOXP3+ Tregs' increased expression may be associated with milder histological lesions. High FOXP3+/CD4+ ratio in the interstitial tissue may have prognostic significance for renal function preservation.
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38
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Fayed A, Mohamed A, Ahmed RA, Abouzeid S, Soliman A, Fathy A. Evaluation of urinary FOXP3 mRNA as a biomarker of lupus nephritis in Egyptian patients with systemic lupus erythematosus. Lupus 2021; 30:1631-1636. [PMID: 34238088 DOI: 10.1177/09612033211030559] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM Lupus nephritis (LN) is one of the most serious complications of SLE. Tregs (Regulatory T lymphocytes) are thought to play a part in the pathogenesis of SLE. According to recent research, Foxp3, a Treg identification marker, plays a significant role in the pathogenesis of SLE. This study aimed to compare the urinary Foxp3 mRNA levels of patients with active and inactive forms of LN and healthy control subjects to see whether it played a role in disease activity. METHODS We measured FOXP3 messenger RNA (mRNA) expression in the urine of 50 people with active LN, 50 people with inactive lupus, and 50 healthy people. RESULTS We found that the expression level of FOXP3 was significantly higher in urine from patients with active LN than from subjects with inactive lupus and healthy controls (22.93 ± 4.13 vs 5.66 ± 0.47 vs 0.57 ± 0.15copy; P < 0.001).Urinary FOXP3 mRNA level significantly correlated with SLEDAI (0.000057) In the active group, urinary FOXP3 mRNA level also significantly correlated with histological activity index (< 0.00001). CONCLUSION We concluded that urinary FOXP3 mRNA is elevated in patients with active LN and that it is linked to the SLEDAI and the severity of the disease. FOXP3 mRNA in urine sediment may be used as a non-invasive biomarker for evaluating the severity of LN and risk stratification.
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Affiliation(s)
- Ahmed Fayed
- Nephrology unit, Internal Medicine Department, Kasr Alainy School of Medicine, Cairo University, Egypt
| | - AbdelAal Mohamed
- Nephrology unit, Internal Medicine Department, Kasr Alainy School of Medicine, Cairo University, Egypt
| | - Reham Abdelghany Ahmed
- Nephrology unit, Internal Medicine Department, Kasr Alainy School of Medicine, Cairo University, Egypt
| | - Sameh Abouzeid
- Nephrology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Ahmed Soliman
- Nephrology unit, Internal Medicine Department, Kasr Alainy School of Medicine, Cairo University, Egypt
| | - Ahmed Fathy
- Nephrology unit, Internal Medicine Department, Kasr Alainy School of Medicine, Cairo University, Egypt
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Baeten P, Van Zeebroeck L, Kleinewietfeld M, Hellings N, Broux B. Improving the Efficacy of Regulatory T Cell Therapy. Clin Rev Allergy Immunol 2021; 62:363-381. [PMID: 34224053 PMCID: PMC8256646 DOI: 10.1007/s12016-021-08866-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2021] [Indexed: 12/11/2022]
Abstract
Autoimmunity is caused by an unbalanced immune system, giving rise to a variety of organ-specific to system disorders. Patients with autoimmune diseases are commonly treated with broad-acting immunomodulatory drugs, with the risk of severe side effects. Regulatory T cells (Tregs) have the inherent capacity to induce peripheral tolerance as well as tissue regeneration and are therefore a prime candidate to use as cell therapy in patients with autoimmune disorders. (Pre)clinical studies using Treg therapy have already established safety and feasibility, and some show clinical benefits. However, Tregs are known to be functionally impaired in autoimmune diseases. Therefore, ex vivo manipulation to boost and stably maintain their suppressive function is necessary when considering autologous transplantation. Similar to autoimmunity, severe coronavirus disease 2019 (COVID-19) is characterized by an exaggerated immune reaction and altered Treg responses. In light of this, Treg-based therapies are currently under investigation to treat severe COVID-19. This review provides a detailed overview of the current progress and clinical challenges of Treg therapy for autoimmune and hyperinflammatory diseases, with a focus on recent successes of ex vivo Treg manipulation.
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Affiliation(s)
- Paulien Baeten
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.,University MS Center, Campus Diepenbeek, Diepenbeek, Belgium
| | - Lauren Van Zeebroeck
- University MS Center, Campus Diepenbeek, Diepenbeek, Belgium.,VIB Laboratory of Translational Immunomodulation, Center for Inflammation Research (IRC), Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Markus Kleinewietfeld
- University MS Center, Campus Diepenbeek, Diepenbeek, Belgium.,VIB Laboratory of Translational Immunomodulation, Center for Inflammation Research (IRC), Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Niels Hellings
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.,University MS Center, Campus Diepenbeek, Diepenbeek, Belgium
| | - Bieke Broux
- Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium. .,University MS Center, Campus Diepenbeek, Diepenbeek, Belgium. .,Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
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40
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Lee LM, Zhang H, Lee K, Liang H, Merleev A, Vincenti F, Maverakis E, Thomson AW, Tang Q. A Comparison of Ex Vivo Expanded Human Regulatory T Cells Using Allogeneic Stimulated B Cells or Monocyte-Derived Dendritic Cells. Front Immunol 2021; 12:679675. [PMID: 34220826 PMCID: PMC8253048 DOI: 10.3389/fimmu.2021.679675] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 06/04/2021] [Indexed: 11/13/2022] Open
Abstract
Alloreactive regulatory T cells (arTregs) are more potent than polyclonal Tregs at suppressing immune responses to transplant antigens. Human arTregs can be expanded with allogeneic CD40L-stimulated B cells (sBcs) or stimulated-matured monocyte-derived dendritic cells (sDCs). Here, we compared the expansion efficiency and properties of arTregs stimulated ex vivo using these two types of antigen-presenting cells. Compared to sBcs, sDCs stimulated Tregs to expand two times more in number. The superior expansion-inducing capacity of sDCs correlated with their higher expression of CD80, CD86, and T cell-attracting chemokines. sBc- and sDC-arTregs expressed comparable levels of FOXP3, HELIOS, CD25, CD27, and CD62L, demethylated FOXP3 enhancer and in vitro suppressive function. sBc- and sDCs-arTregs had similar gene expression profiles that were distinct from primary Tregs. sBc- and sDC-arTregs exhibited similar low frequencies of IFN-γ, IL-4, and IL-17A-producing cells, and the cytokine-producing arTregs expressed high levels of FOXP3. Almost all sBc- and sDC-arTregs expressed CXCR3, which may enable them traffic to inflammatory sites. Thus, sDCs-arTregs that expand more readily, are phenotypically similar to sBc-arTregs, supporting sDCs as a viable alternative for arTreg production for clinical evaluation.
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Affiliation(s)
- Linda M Lee
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Hong Zhang
- Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States
| | - Karim Lee
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Horace Liang
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Alexander Merleev
- Department of Dermatology, School of Medicine, University of California Davis, Davis, CA, United States
| | - Flavio Vincenti
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States.,Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Emanual Maverakis
- Department of Dermatology, School of Medicine, University of California Davis, Davis, CA, United States
| | - Angus W Thomson
- Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Qizhi Tang
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
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Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis. Hepatobiliary Pancreat Dis Int 2021; 20:207-214. [PMID: 33972160 DOI: 10.1016/j.hbpd.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 04/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αβ) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.
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42
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Lu J, Li P, Du X, Liu Y, Zhang B, Qi F. Regulatory T cells induce transplant immune tolerance. Transpl Immunol 2021; 67:101411. [PMID: 34020045 DOI: 10.1016/j.trim.2021.101411] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/14/2021] [Accepted: 05/16/2021] [Indexed: 01/03/2023]
Abstract
Organ transplantation is the preferred treatment option for end-stage organ failure. Although immunosuppressants are effective for preventing the occurrence of acute rejection, they also cause a series of side effects in transplant recipients. To improve the quality of patient survival, a new therapeutic strategy that has fewer side effects than current immunosuppressive regimens and can induce allograft immune tolerance and effectively prevent transplant rejection is needed. In this context, regulatory T cells (Tregs) are considered to be promising research targets. With the increasing understanding of the immunomodulatory role of Tregs, the use of Treg-based cellular therapies has shifted from prevention/treatment of autoimmune diseases to clinical trials for organ transplantation. This review describes the phenotype and in vitro expansion of Tregs and the mechanisms by which they exert immunomodulatory effects in transplantation immunity, highlights recent clinical trial data on Treg-based cellular therapies in transplantation, and describes future directions and limitations.
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Affiliation(s)
- Jian Lu
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China; Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, Anhui 230022, China.
| | - Peiyuan Li
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China.
| | - Xuezhi Du
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China.
| | - Yanhong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China.
| | - Baotong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China.
| | - Feng Qi
- Department of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Heping District, Tianjin 300052, China.
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Excessive Innate Immunity Steers Pathogenic Adaptive Immunity in the Development of Theiler's Virus-Induced Demyelinating Disease. Int J Mol Sci 2021; 22:ijms22105254. [PMID: 34067536 PMCID: PMC8156427 DOI: 10.3390/ijms22105254] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/06/2021] [Accepted: 05/13/2021] [Indexed: 01/05/2023] Open
Abstract
Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.
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Teer E, Joseph DE, Dominick L, Glashoff RH, Essop MF. Expansion of GARP-Expressing CD4 +CD25 -FoxP3 + T Cells and SATB1 Association with Activation and Coagulation in Immune Compromised HIV-1-Infected Individuals in South Africa. Virol Sin 2021; 36:1133-1143. [PMID: 33974229 DOI: 10.1007/s12250-021-00386-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 02/23/2021] [Indexed: 11/24/2022] Open
Abstract
Although antiretroviral treatment lowers the burden of human immunodeficiency virus (HIV)-related disease, it does not always result in immunological recovery. This manifests as persistent chronic inflammation, immune activation or exhaustion that can promote the onset of co-morbidities. As the exact function of regulatory T (Treg) cells in HIV remains unclear, this cross-sectional study investigated three expression markers (Forkhead box protein P3 [FOXP3], glycoprotein A repetitions predominant [GARP], special AT-rich sequence binding protein 1 [SATB1]) and compared their expansion between CD4+CD25- and CD4+CD25++ T cells. Age-matched study subjects were recruited (Western Cape, South Africa) and sub-divided: HIV-negative subjects (n = 12), HIV-positive naïve treated (n = 22), HIV-positive treated based on CD4 count cells/µL (CD4 > 500 and CD4 < 500) (n = 34) and HIV-treated based on viral load (VL) copies/mL (VL < 1000 and VL > 1000) (n = 34). Markers of immune activation (CD38) and coagulation (CD142) on T cells (CD8) were assessed by flow cytometry together with FOXP3, GARP and SATB1 expression on CD4+CD25- and CD4+CD25++ T cells. Plasma levels of interleukin-10 (IL-10; anti-inflammatory marker), IL-6 (inflammatory marker) and D-dimer (coagulation marker) were assessed. This study revealed three major findings in immuno-compromised patients with virological failure (CD4 < 500; VL > 1000): (1) the expansion of the unconventional Treg cell subset (CD4+CD25-FOXP3+) is linked with disease progression markers; (2) increased GARP expression in the CD4+CD25- and CD4+CD25++ subsets; and (3) the identification of a strong link between CD4+CD25-SATB1+ cells and markers of immune activation (CD8+CD38+) and coagulation (CD8+CD142+ and D-dimer).
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Affiliation(s)
- Eman Teer
- Centre for Cardio-Metabolic Research in Africa (CARMA), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa
| | - Danzil E Joseph
- Centre for Cardio-Metabolic Research in Africa (CARMA), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa
| | - Leanne Dominick
- Centre for Cardio-Metabolic Research in Africa (CARMA), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa
| | - Richard H Glashoff
- Division of Medical Microbiology and Immunology, Department of Pathology, Stellenbosch University and NHLS, Cape Town, 7505, South Africa
| | - M Faadiel Essop
- Centre for Cardio-Metabolic Research in Africa (CARMA), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa.
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Jin J, Li Y, Zhao Q, Chen Y, Fu S, Wu J. Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression. Cell Commun Signal 2021; 19:50. [PMID: 33957948 PMCID: PMC8101191 DOI: 10.1186/s12964-021-00705-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/11/2021] [Indexed: 12/24/2022] Open
Abstract
Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed the tumor microenvironment (TME) immune cells to functionally affect the development and progression of breast cancer. However, insufficient evidence of TME immune modulators limit the clinical application of immunotherapy for advanced and metastatic breast cancers. Intercellular STAT3 activation of immune cells plays a central role in breast cancer TME immunosuppression and distant metastasis. Accumulating evidence suggests that targeting STAT3 and/or in combination with radiotherapy may enhance anti-cancer immune responses and rescue the systemic immunologic microenvironment in breast cancer. Indeed, apart from its oncogenic role in tumor cells, the functions of STAT3 in TME of breast cancer involve multiple types of immunosuppression and is associated with tumor cell metastasis. In this review, we summarize the available information on the functions of STAT3-related immune cells in TME of breast cancer, as well as the specific upstream and downstream targets. Additionally, we provide insights about the potential immunosuppression mechanisms of each type of evaluated immune cells. Video abstract.
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Affiliation(s)
- Jing Jin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan People’s Republic of China
| | - Yi Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan People’s Republic of China
| | - Qijie Zhao
- Department of Radiologic Technology, Center of Excellence for Molecular Imaging (CEMI), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200 Thailand
- Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou, 646000 Sichuan People’s Republic of China
| | - Yue Chen
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, 646000 Sichuan People’s Republic of China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, 646000 Sichuan People’s Republic of China
| | - Shaozhi Fu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan People’s Republic of China
| | - JingBo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000 Sichuan People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, 646000 Sichuan People’s Republic of China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, 646000 Sichuan People’s Republic of China
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Single-cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4 + T cell perturbations. Nat Immunol 2021; 22:607-619. [PMID: 33833438 PMCID: PMC8173714 DOI: 10.1038/s41590-021-00910-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 02/26/2021] [Indexed: 01/31/2023]
Abstract
FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.
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47
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Dolina JS, Lee J, Griswold RQ, Labarta-Bajo L, Kannan S, Greenbaum JA, Bahia El Idrissi N, Pont MJ, Croft M, Schoenberger SP. TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4 + T Cells to T reg. Cell Rep 2021; 31:107249. [PMID: 32268093 PMCID: PMC8903023 DOI: 10.1016/j.celrep.2020.01.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 12/02/2019] [Accepted: 01/10/2020] [Indexed: 12/12/2022] Open
Abstract
CD4+ T lymphocytes are crucial for controlling a range of innate and adaptive immune effectors. For CD8+ cytotoxic T lymphocyte (CTL) responses, CD4+ T cells can function as helpers (TH) to amplify magnitude and functionality or as regulatory cells (Treg) capable of profound inhibition. It is unclear what determines differentiation to these phenotypes and whether pathogens provoke alternate programs. We find that, depending on the size of initial dose, Listeria infection drives CD4+ T cells to act as TH or induces rapid polyclonal conversion to immunosuppressive Treg. Conversion to Treg depends on the TLR9 and IL-12 pathways elicited by CD8a+ dendritic cell (DC) sensing of danger-associated neutrophil self-DNA. These findings resolve long-standing questions regarding the conditional requirement for TH amongst pathogens and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Tregin vivo by infection-mediated immune modulation. Dolina et al. show that Listeria infectious dose drives conventional CD4+ T cells to act as TH or mediates conversion to Treg. Differentiation to Treg dominates heightened doses and is promoted by CD8α+ DC TLR9 engagement of neutrophil self-DNA and IL-12 production, revealing plasticity in the function of CD4+ T cells.
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Affiliation(s)
- Joseph S Dolina
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
| | - Joey Lee
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Ryan Q Griswold
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Lara Labarta-Bajo
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Section of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sumetha Kannan
- Bioinformatics Core, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Jason A Greenbaum
- Bioinformatics Core, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Nawal Bahia El Idrissi
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Neurogenetics, Academic Medical Center, Amsterdam, the Netherlands
| | - Margot J Pont
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Michael Croft
- Division of Immune Regulation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Stephen P Schoenberger
- Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
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Glasner A, Plitas G. Tumor resident regulatory T cells. Semin Immunol 2021; 52:101476. [PMID: 33906820 DOI: 10.1016/j.smim.2021.101476] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/08/2021] [Accepted: 04/13/2021] [Indexed: 02/08/2023]
Abstract
The immune system mediates powerful effector mechanisms to protect against a diversity of pathogens and equally as important regulatory functions, to limit collateral damage of inflammation, prevent misguided immune responses to "self", and promote tissue repair. Inadequate regulatory control can lead to a variety of inflammatory disorders including autoimmunity, metabolic syndrome, allergies, and progression of malignancies. Cancers evolve complex mechanisms to thwart immune eradication including coopting normal host regulatory processes. This is most evident in the analysis of tumor infiltrating lymphocytes (TILs), where a preponderance of immunosuppressive immune cells, such as regulatory T (Treg) cells are found. Treg cells express the X-chromosome linked transcription factor Foxp3 and play a crucial role in maintaining immune homeostasis by suppressing inflammatory responses in diverse biological settings. Treg cells in the tumor microenvironment promote tumor development and progression by dampening anti-tumor immune responses, directly supporting the survival of transformed cells through elaboration of growth factors, and interacting with accessory cells in tumors such as fibroblasts and endothelial cells. Current insights into the phenotype and function of tumor associated Treg cells have opened up opportunities for their selective targeting in cancer with the goal of alleviating their suppression of anti-tumor immune responses while maintaining overall immune homeostasis. Here, we review Treg cell biology in the context of the tumor microenvironment (TME), and the important role they play in cancer immunotherapy.
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Affiliation(s)
- Ariella Glasner
- Immunology Program and Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - George Plitas
- Immunology Program and Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA; Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
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Lymphopenia, Lymphopenia-Induced Proliferation, and Autoimmunity. Int J Mol Sci 2021; 22:ijms22084152. [PMID: 33923792 PMCID: PMC8073364 DOI: 10.3390/ijms22084152] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival of an individual. How the defects in this system might result in autoimmunity is discussed in this review. Reduced lymphocyte number, termed lymphopenia, can mediate lymphopenia-induced proliferation (LIP) to maintain peripheral lymphocyte numbers. LIP not only occurs in normal physiological conditions but also correlates with autoimmunity. Of note, lymphopenia is also a typical marker of immune aging, consistent with the fact that not only the autoimmunity increases in the elderly, but also autoimmune diseases (ADs) show characteristics of immune aging. Here, we discuss the types and rates of LIP in normal and autoimmune conditions, as well as the coronavirus disease 2019 in the context of LIP. Importantly, although the causative role of LIP has been demonstrated in the development of type 1 diabetes and rheumatoid arthritis, a two-hit model has suggested that the factors other than lymphopenia are required to mediate the loss of control over homeostasis to result in ADs. Interestingly, these factors may be, if not totally, related to the function/number of regulatory T cells which are key modulators to protect from self-reactivity. In this review, we summarize the important roles of lymphopenia/LIP and the Treg cells in various autoimmune conditions, thereby highlighting them as key therapeutic targets for autoimmunity treatments.
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50
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Tietze S, Michen S, Schackert G, Temme A. Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma. Innov Surg Sci 2021. [DOI: 10.1515/iss-2020-0034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Abstract
Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.
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Affiliation(s)
- Stefanie Tietze
- Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology , University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany
| | - Susanne Michen
- Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology , University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany
| | - Gabriele Schackert
- Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology , University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany
- German Cancer Consortium (DKTK) , Dresden , Germany
- German Cancer Research Center (DKFZ) , Heidelberg , Germany
- National Center for Tumor Diseases , University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany
| | - Achim Temme
- Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology , University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany
- German Cancer Consortium (DKTK) , Dresden , Germany
- German Cancer Research Center (DKFZ) , Heidelberg , Germany
- National Center for Tumor Diseases , University Hospital Carl Gustav Carus, Technical University Dresden , Dresden , Germany
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