|
1
|
Liu Y, Li D, Zhang X, Xia S, Qu Y, Ling X, Li Y, Kong X, Zhang L, Cui CP, Li D. A protein sequence-based deep transfer learning framework for identifying human proteome-wide deubiquitinase-substrate interactions. Nat Commun 2024; 15:4519. [PMID: 38806474 PMCID: PMC11133436 DOI: 10.1038/s41467-024-48446-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 04/26/2024] [Indexed: 05/30/2024] Open
Abstract
Protein ubiquitination regulates a wide range of cellular processes. The degree of protein ubiquitination is determined by the delicate balance between ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination. In comparison to the E3-substrate interactions, the DUB-substrate interactions (DSIs) remain insufficiently investigated. To address this challenge, we introduce a protein sequence-based ab initio method, TransDSI, which transfers proteome-scale evolutionary information to predict unknown DSIs despite inadequate training datasets. An explainable module is integrated to suggest the critical protein regions for DSIs while predicting DSIs. TransDSI outperforms multiple machine learning strategies against both cross-validation and independent test. Two predicted DUBs (USP11 and USP20) for FOXP3 are validated by "wet lab" experiments, along with two predicted substrates (AR and p53) for USP22. TransDSI provides new functional perspective on proteins by identifying regulatory DSIs, and offers clues for potential tumor drug target discovery and precision drug application.
Collapse
Affiliation(s)
- Yuan Liu
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Dianke Li
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Xin Zhang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Simin Xia
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yingjie Qu
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xinping Ling
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- College of Life Sciences, Hebei University, Baoding, 071002, China
| | - Yang Li
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xiangren Kong
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Lingqiang Zhang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Chun-Ping Cui
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Dong Li
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| |
Collapse
|
|
2
|
Nicola Candia AJ, Garcia Fallit M, Peña Agudelo JA, Pérez Küper M, Gonzalez N, Moreno Ayala MA, De Simone E, Giampaoli C, Casares N, Seilicovich A, Lasarte JJ, Zanetti FA, Candolfi M. Targeting FOXP3 Tumor-Intrinsic Effects Using Adenoviral Vectors in Experimental Breast Cancer. Viruses 2023; 15:1813. [PMID: 37766222 PMCID: PMC10537292 DOI: 10.3390/v15091813] [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: 07/24/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023] Open
Abstract
The regulatory T cell master transcription factor, Forkhead box P3 (Foxp3), has been detected in cancer cells; however, its role in breast tumor pathogenesis remains controversial. Here we assessed Foxp3 tumor intrinsic effects in experimental breast cancer using a Foxp3 binder peptide (P60) that impairs Foxp3 nuclear translocation. Cisplatin upregulated Foxp3 expression in HER2+ and triple-negative breast cancer (TNBC) cells. Foxp3 inhibition with P60 enhanced chemosensitivity and reduced cell survival and migration in human and murine breast tumor cells. We also developed an adenoviral vector encoding P60 (Ad.P60) that efficiently transduced breast tumor cells, reduced cell viability and migration, and improved the cytotoxic response to cisplatin. Conditioned medium from transduced breast tumor cells contained lower levels of IL-10 and improved the activation of splenic lymphocytes. Intratumoral administration of Ad.P60 in breast-tumor-bearing mice significantly reduced tumor infiltration of Tregs, delayed tumor growth, and inhibited the development of spontaneous lung metastases. Our results suggest that Foxp3 exerts protumoral intrinsic effects in breast cancer cells and that gene-therapy-mediated blockade of Foxp3 could constitute a therapeutic strategy to improve the response of these tumors to standard treatment.
Collapse
Affiliation(s)
- Alejandro J. Nicola Candia
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| | - Matías Garcia Fallit
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina
| | - Jorge A. Peña Agudelo
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| | - Melanie Pérez Küper
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| | - Nazareno Gonzalez
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| | - Mariela A. Moreno Ayala
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| | - Emilio De Simone
- Cátedra de Fisiología Animal, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires C1428BFA, Argentina
| | - Carla Giampaoli
- Cátedra de Fisiología Animal, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires C1428BFA, Argentina
| | - Noelia Casares
- Program Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA, CUN), 31008 Pamplona, Spain; (N.C.)
- Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain
| | - Adriana Seilicovich
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| | - Juan José Lasarte
- Program Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA, CUN), 31008 Pamplona, Spain; (N.C.)
- Instituto de Investigación Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain
| | - Flavia A. Zanetti
- Instituto de Ciencia y Tecnología “Dr. Cesar Milstein”, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Saladillo C1440FFX, Buenos Aires, Argentina;
| | - Marianela Candolfi
- Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121A6B, Argentina; (A.J.N.C.); (A.S.)
| |
Collapse
|
|
3
|
Wang F, Yang Y, Li Z, Wang Y, Zhang Z, Zhang W, Mu Y, Yang J, Yu L, Wang M. Mannan-Binding Lectin Regulates the Th17/Treg Axis Through JAK/STAT and TGF-β/SMAD Signaling Against Candida albicans Infection. J Inflamm Res 2022; 15:1797-1810. [PMID: 35300210 PMCID: PMC8923702 DOI: 10.2147/jir.s344489] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/08/2022] [Indexed: 12/04/2022] Open
Abstract
Background Mannan-binding lectin (MBL) is a key molecule in innate immunity and activates the lectin complement pathway, which plays an important role in resisting Candida albicans (C. albicans) infection. However, the underlying mechanism of this resistance to infection remains unclear. Methods In this study, we investigated how MBL regulates the differentiation of CD4+ T cells into T helper type 17 (Th17) and T regulatory (Treg) cells against C. albicans in mice, as well as the underlying mechanisms. We generated MBL double-knockout (KO) mice and infected them with C. albicans by intraperitoneal injection. Results Compared with that in wild-type (WT) mice, the percentage of Th17 cells increased in MBL-null mice, whereas Treg cells decreased, indicating that MBL might regulate the Th17/Treg balance. In addition, in MBL-null mice, the expression levels of interleukin (IL)-17A, IL-21, and the master transcription factor of Th17 cells, RORγt, significantly increased. Conversely, IL-10, IL-2, and the Treg-specific transcription factor, Foxp3, decreased. Moreover, we found that the levels of TGF-β and IL-6 upregulated in MBL-null mice. Mechanistically, we found that MBL regulated the TGF-β/SMAD pathway through the inhibition of p-SMAD2 and promotion of p-SMAD3, and mediated the JAK/STAT pathway through the inhibition of p-JAK2 and p-STAT3 and promotion of p-JAK3 and p-STAT5. MBL double-KO mice showed a more severe inflammatory response and significantly lower survival rates with C. albicans infection. Conclusion These results suggest that MBL regulates the Th17/Treg cell balance to inhibit inflammatory responses, possibly via IL-6- and TGF-β-mediated JAK/STAT and TGF-β/SMAD signaling, and play an important role in anti-C. albicans infection.
Collapse
Affiliation(s)
- Fanping Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Yonghui Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Henan Center for Disease Control and Prevention, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Zhixin Li
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Yan Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Department of Laboratory Medicine, Luoyang Oriental Hospital, Luoyang, Henan, 471000, People’s Republic of China
| | - Zhenchao Zhang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Wei Zhang
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Yonghui Mu
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Jingwen Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
| | - Lili Yu
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
| | - Mingyong Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China
- Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China
- Correspondence: Mingyong Wang; Lili Yu, Email ;
| |
Collapse
|
|
4
|
Razazian M, Khosravi M, Bahiraii S, Uzan G, Shamdani S, Naserian S. Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells. World J Stem Cells 2021; 13:971-984. [PMID: 34567420 PMCID: PMC8422932 DOI: 10.4252/wjsc.v13.i8.971] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/28/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders. Although both cell populations have been already studied and used for their regenerative potentials, recently their special immunoregulatory features have brought much more attention. Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response, particularly T cell proliferation, activation, and cytokine production. This makes them suitable choices for allogeneic stem cell transplantation. Nevertheless, these two cells do not have equal immunoregulatory activities. Many elements including their extraction sources, age/passage, expression of different markers, secretion of bioactive mediators, and some others could change the efficiency of their immunosuppressive function. However, to our knowledge, no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells. This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression, deactivation, cytokine production, and regulatory T cells induction capacities. Moreover, it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.
Collapse
Affiliation(s)
- Mehdi Razazian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
| | - Maryam Khosravi
- Microenvironment & Immunity Unit, Institut Pasteur, Paris 75724, France
- Institut national de la santé et de la recherche médicale (Inserm) Unit 1224, Paris 75724, France
| | - Sheyda Bahiraii
- Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria
| | - Georges Uzan
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
| | - Sara Shamdani
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France
| | - Sina Naserian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France.
| |
Collapse
|
|
5
|
Zhang S, Gan X, Qiu J, Ju Z, Gao J, Zhou J, Shi C, Zhu Y, Li Z. IL-10 derived from Hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment. Mol Immunol 2021; 133:163-172. [PMID: 33667986 DOI: 10.1016/j.molimm.2021.02.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/09/2020] [Accepted: 02/15/2021] [Indexed: 12/12/2022]
Abstract
Forkhead box P3 (Foxp3) expressing CD4+CD25+ regulatory T cells (Tregs), an essential subset of immune T cells for maintaining immune homeostasis is implicated as a negative regulator in an anti-tumor immune response. Current researches suggest that reducing tumor-infiltrating Tregs contribute to enhanced anti-cancer effect. However, the mechanism of infiltration of a large number of Tregs into tumor tissues is still unclear. In this study, human induced Tregs (iTregs) were co-cultured with human hepatocytes and various types of cancer cells (HepG2, NSCLC, and AsPC-1) supernatants. Foxp3, multiple cytokines, levels of apoptosis and suppressive ability of iTregs were detected by FACS. Western blot was employed to test of proteins. Impact of HepG2 supernatants on T cell subpopulations differentiation, cytokines in supernatants were examed by FACS and ELISA respectively. Anti-IL-10R antibody and JAK1 inhibitor were used to reconfirm the role of tumor-derived IL-10 play in the regulation on iTregs. Hepatocarcinoma cells (HCC) supernatants treatment increases Foxp3 stability and reduces apoptosis level in human iTregs without influencing its differentiation trend. Furthermore, IL-10 was found to be extremely higher in HCC supernatants than other groups, IL-10R blockade neutralize the effect of HCC supernatants on iTregs in vitro obviously. HCC supernatants also reversed IL-1β/6 triggered decline on Foxp3 which may be related to higher expression of JAK1 and elevated phosphorylation level of STAT5 induced by IL-10. Our results suggest that improved stability and abnormal accumulation of Tregs in tumor microenvironment is IL-10/JAK1/STAT5 signal pathway-dependent and provide a novel approach for improving the efficiency of anti-tumor immunotherapy.
Collapse
Affiliation(s)
- Shaopeng Zhang
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaojie Gan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, 200438, China
| | - Jiannan Qiu
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zheng Ju
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ji Gao
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jinren Zhou
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Chengyu Shi
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yaqing Zhu
- Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Zhang Li
- Department of Hepatobiliary and Pancreatic Surgery, LiYang People's Hospital, No 70 Jianshe Westroad, LiYang, 213300, Jiangsu, China; Research Unit of Liver Transplantation and Transplant Immunology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| |
Collapse
|
|
6
|
Bailey C, Segner H, Wahli T, Tafalla C. Back From the Brink: Alterations in B and T Cell Responses Modulate Recovery of Rainbow Trout From Chronic Immunopathological Tetracapsuloides bryosalmonae Infection. Front Immunol 2020; 11:1093. [PMID: 32582181 PMCID: PMC7283781 DOI: 10.3389/fimmu.2020.01093] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
Proliferative kidney disease (PKD) caused by the myxozoan parasite Tetracapsuloides bryosalmonae is one of the most serious infectious diseases negatively impacting farmed and wild salmonids throughout Europe and North America. PKD pathogenesis results in a massive B cell proliferation and dysregulation with aberrant immunoglobulin production and plasma cell differentiation along with a decrease in myeloid cells and inhibition of innate pathways. Despite the huge immunopathological reaction in the kidney during infection, under specific conditions, fish can survive and return to full fitness. Fish are unique in this ability to recover renal structure and functionality from extensive tissue damage in contrast to mammals. However, only limited knowledge exists regarding the host immune response coinciding with PKD recovery. Moreover, almost no studies of the immune response during disease recovery exist in fish. We utilized the rainbow trout-T. bryosalmonae system as an immunological model of disease recovery. Our results demonstrated that recovery is preceded by an intense immune response at the transcript level, decreasing parasite burden, and an increased degree of kidney inflammation. Later in the recovery phase, the immune response transpired with a significant decrease in lymphocytes and an increase in myeloid cells. These lymphocytes populations contained lower levels of B cells comparative to the control in the anterior and posterior kidney. Additionally, there was downregulation of several transcripts used as markers for plasma cells (blimp1, igt sec, igm sec, igd sec, and cd38) and T cell subsets (cd4, cd8α, cd8β, and tcrβ). The decrease in these T cell transcripts significantly correlated with decreasing parasite intensity. Alternatively, there was strong upregulation of pax-5 and igt mem. This suggests a change in B cell processes during the recovery phase relative to clinical PKD may be necessary for the host to re-establish homeostasis in terms of an arrest in the dominant antibody like response transitioning to a transcriptional profile associated with resting B cells. The knowledge generated here in combination with earlier studies illuminates the full power of analyzing the entire trajectory of disease from the normal healthy state to recovery enabling the measurement of an immune response to pinpoint a specific disease stage.
Collapse
Affiliation(s)
- Christyn Bailey
- Fish Immunology and Pathology Group, Animal Health Research Center (CISA-INIA), Madrid, Spain
| | - Helmut Segner
- Centre for Fish and Wildlife Health, University of Bern, Bern, Switzerland
| | - Thomas Wahli
- Centre for Fish and Wildlife Health, University of Bern, Bern, Switzerland
| | - Carolina Tafalla
- Fish Immunology and Pathology Group, Animal Health Research Center (CISA-INIA), Madrid, Spain
| |
Collapse
|
|
7
|
Age-related transcriptional modules and TF-miRNA-mRNA interactions in neonatal and infant human thymus. PLoS One 2020; 15:e0227547. [PMID: 32294112 PMCID: PMC7159188 DOI: 10.1371/journal.pone.0227547] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 12/18/2019] [Indexed: 12/15/2022] Open
Abstract
The human thymus suffers a transient neonatal involution, recovers and then starts a process of decline between the 1st and 2nd years of life. Age-related morphological changes in thymus were extensively investigated, but the genomic mechanisms underlying this process remain largely unknown. Through Weighted Gene Co-expression Network Analysis (WGCNA) and TF-miRNA-mRNA integrative analysis we studied the transcriptome of neonate and infant thymic tissues grouped by age: 0–30 days (A); 31days-6 months (B); 7–12 months (C); 13–18 months (D); 19-31months (E). Age-related transcriptional modules, hubs and high gene significance (HGS) genes were identified, as well as TF-miRNA-hub/HGS co-expression correlations. Three transcriptional modules were correlated with A and/or E groups. Hubs were mostly related to cellular/metabolic processes; few were differentially expressed (DE) or related to T-cell development. Inversely, HGS genes in groups A and E were mostly DE. In A (neonate) one third of the hyper-expressed HGS genes were related to T-cell development, against one-twentieth in E, what may correlate with the early neonatal depletion and recovery of thymic T-cell populations. This genomic mechanism is tightly regulated by TF-miRNA-hub/HGS interactions that differentially govern cellular and molecular processes involved in the functioning of the neonate thymus and in the beginning of thymic decline.
Collapse
|
|
8
|
Abstract
Three decades of research in hematopoietic stem cell transplantation and HIV/AIDS fields have shaped a picture of immune restoration disorders. This manuscript overviews the molecular biology of interferon networks, the molecular pathogenesis of immune reconstitution inflammatory syndrome, and post-hematopoietic stem cell transplantation immune restoration disorders (IRD). It also summarizes the effects of thymic involution on T cell diversity, and the results of the assessment of diagnostic biomarkers of IRD, and tested targeted immunomodulatory treatments.
Collapse
Affiliation(s)
- Hesham Mohei
- Department of Medicine, University of Minnesota, Minneapolis, USA
| | - Usha Kellampalli
- Department of Medicine, University of Minnesota, Minneapolis, USA
| | | |
Collapse
|
|
9
|
Ferrandino F, Grazioli P, Bellavia D, Campese AF, Screpanti I, Felli MP. Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer. Front Immunol 2018; 9:2165. [PMID: 30364244 PMCID: PMC6193072 DOI: 10.3389/fimmu.2018.02165] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/03/2018] [Indexed: 12/20/2022] Open
Abstract
The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.
Collapse
Affiliation(s)
| | - Paola Grazioli
- Department of Experimental Medicine, La Sapienza University, Rome, Italy
| | - Diana Bellavia
- Department of Molecular Medicine, La Sapienza University, Rome, Italy
| | | | | | - Maria Pia Felli
- Department of Experimental Medicine, La Sapienza University, Rome, Italy
| |
Collapse
|
|
10
|
Skarmoutsou E, Bevelacqua V, D' Amico F, Russo A, Spandidos DA, Scalisi A, Malaponte G, Guarneri C. FOXP3 expression is modulated by TGF‑β1/NOTCH1 pathway in human melanoma. Int J Mol Med 2018; 42:392-404. [PMID: 29620159 PMCID: PMC5979787 DOI: 10.3892/ijmm.2018.3618] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 04/04/2018] [Indexed: 12/18/2022] Open
Abstract
Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability.
Collapse
Affiliation(s)
- Eva Skarmoutsou
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Valentina Bevelacqua
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Fabio D' Amico
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Angela Russo
- Department of Biomedical and Biotechnological Science, University of Catania, 95124 Catania, Italy
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP‑Catania, 95100 Catania, Italy
| | - Grazia Malaponte
- Research Unit of the Catania Section of the Italian League Against Cancer, 95122 Catania, Italy
| | - Claudio Guarneri
- Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, 98122 Messina, Italy
| |
Collapse
|
|
11
|
Akbari Z, Taheri M, Jafari A, Sayad A. FOXP3 gene expression in the blood of Iranian multiple sclerosis patients. Hum Antibodies 2018. [PMID: 29526847 DOI: 10.3233/hab-180334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Multiple sclerosis (MS) is a heterogeneous disease with an unknown etiology. Both genetic and environmental factors lead to MS disease. Recent studies have revealed the inhibitory role of T regulatory cells in the MS disease. Forkhead box P3 (FOXP3) gene is a transcript of the CD4+CD25+FOXP3 and T regulatory cells that is recently introduced as a factor in determining the lineage of immune cells. Based on these assumptions we investigate the expression of this gene in the peripheral blood of fifty MS patients in comparison to fifty controls. MATERIAL AND METHODS In this case-control study, we investigate the FOXP3 expression in fifty MS patients (30 females (60%) and 20 males (40%), mean age ± SD: 33.3 ± 5.4 years) in comparing to fifty healthy age and sex matched-controls (30 females (60%) and 20 males (40%), mean age ± SD: 34.2 ± 4.8) using real-time quantitative reverse transcription-PCR (qRT-PCR) in order to explore any association between FOXP3 expression level and MS. RESULTS The expression level of FOXP3 gene was not significantly different between MS patients and controls (p: 0.79). In addition the expression level of the gene was not significantly different between male and female (p: 0.8, p: 0.79, respectively). CONCLUSION Although, the FOXP3 gene is one of the most important genes in the regulation of the immune cells, according to no significant results of this study it may concluded that the expression of the gene is not different between MS patients and healthy controls at least at mRNA level. So it seems that investigating the protein level of FOXP3, related LNCs and microRNAs could be useful to investigate the relation between this gene and the disease. However, the clinical relevance of FOXP3 in patients with regard to their therapy needs to be further explored by evaluation of genetic background in relation to immune responses in MS patients.
Collapse
Affiliation(s)
- Zahra Akbari
- Department of Biology, Arsanjan Branch, Islamic Azad University, Arsanjan, Iran
| | - Mohammad Taheri
- Department of Medical Genetics, Shahid Beheshti University of Medical sciences, Tehran, Iran.,Urogenital Stem Cell Research, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdorreza Jafari
- Department of Biology, Arsanjan Branch, Islamic Azad University, Arsanjan, Iran
| | - Arezou Sayad
- Department of Medical Genetics, Shahid Beheshti University of Medical sciences, Tehran, Iran
| |
Collapse
|
|
12
|
Yang L, Guo W, Zhang S, Wang G. Ubiquitination-proteasome system: A new player in the pathogenesis of psoriasis and clinical implications. J Dermatol Sci 2017; 89:219-225. [PMID: 29279285 DOI: 10.1016/j.jdermsci.2017.12.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 12/11/2017] [Indexed: 12/13/2022]
Abstract
Ubiquitination is an important post-translational modification that regulates a myriad of biological processes such as inflammation, immune response, cell differentiation and proliferation. During the last decade, progress in proteomics contributed to the identification of new E3 ligases and their substrates. Hence, deregulated ubiquitination events are found to be involved in several inflammatory disorders, exemplifying by systemic lupus erythematosus (SLE), type 1 diabetes, rheumatoid arthritis (RA) and psoriasis. Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and differentiation. Through regulation of key transcriptional factors or signaling members, ubiquitination is viewed as a key regulator in psoriasis. Thus, targeting ubiquitination pathway holds potential for the treatment of psoriasis. Herein, we summarize the current understanding of ubiquitination in psoriasis, and discuss the prospects for targeting ubiquitination in the treatment of psoriasis.
Collapse
Affiliation(s)
- Luting Yang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Weinan Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shaolong Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
| |
Collapse
|
|
13
|
Zhang D, Chen Y, Chen L, Yang R, Wang L, Liu W, Zhai Z, Shen Z. Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis. Exp Dermatol 2016; 25:513-8. [PMID: 26781862 DOI: 10.1111/exd.12942] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2016] [Indexed: 02/03/2023]
Abstract
The decrease of forkhead box P3-positive (FOXP3 + ) regulatory T cells (Tregs) causes an immune imbalance with effector T cells in psoriasis. Previous studies have demonstrated that in addition to its known effects on keratinocytes and effector T cells, ultraviolet (UV) irradiation alleviates psoriasis via the upregulation of FOXP3 + Tregs. However, the mechanism is unclear. Here, we found that FOXP3 + T cells were increased in psoriatic lesions after UVB irradiation (t' = 3.7006, P < 0.01), as determined by immunohistochemical staining. In addition, the levels of FOXP3 and p53, one of the downstream targets of UV irradiation, showed accordant changes after UV irradiation. Experiments that used a MAPK inhibitor, p53 mutant cell lines, p53 inhibitor and p53 shRNA showed a decrease in FOXP3 levels, suggesting that p53 is required for UV-induced FOXP3 transcription. Next, we demonstrated that there are two binding sites for p53 on FOXP3 by informatics tools, a dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. One binding site (-1771 to -1583) is located at the promoter region and is adjacent to a previously reported p53-binding region in breast cancer cells. The other (+3845 to +4042) is located within the first intron and has not been previously reported. Our study demonstrated that FOXP3 is regulated, at least in part, by the binding of p53 to several binding sites in the promoter and intron regions following UV irradiation in psoriasis. It will be helpful to further clarify the regulatory mechanism of FOXP3 transcription and to provide new insights into the mechanisms that mediate the effects of UV irradiation in autoimmune skin disorders.
Collapse
Affiliation(s)
- Dongmei Zhang
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yang Chen
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ling Chen
- Department of Dermatology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Riyao Yang
- Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, USA
| | - Li Wang
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Wenying Liu
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhifang Zhai
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhu Shen
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
|
14
|
Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A, Ko J, Novack DV, DiPaolo R, Aurora R. A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells. J Bone Miner Res 2015; 30:1508-22. [PMID: 25656537 PMCID: PMC4506715 DOI: 10.1002/jbmr.2472] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 01/15/2015] [Accepted: 01/30/2015] [Indexed: 12/30/2022]
Abstract
TNF-α and IL-17 secreted by proinflammatory T cells (T(EFF)) promote bone erosion by activating osteoclasts. We previously demonstrated that in addition to bone resorption, osteoclasts act as antigen-presenting cells to induce FoxP3 in CD8 T cells (Tc(REG)). The osteoclast-induced regulatory CD8 T cells limit bone resorption in ovariectomized mice (a murine model of postmenopausal osteoporosis). Here we show that although low-dose receptor activator of NF-κB ligand (RANKL) maximally induces Tc(REG) via Notch signaling pathway to limit bone resorption, high-dose RANKL promotes bone resorption. In vitro, both TNF-α and IL-17, cytokines that are abundant in ovariectomized animals, suppress Tc(REG) induction by osteoclasts by repressing Notch ligand expression in osteoclasts, but this effect can be counteracted by addition of RANKL. Ovariectomized mice treated with low-dose RANKL induced Tc(REG) that suppressed bone resorption, decreased T(EFF) levels, and increased bone formation. High-dose RANKL had the expected osteolytic effect. Low-dose RANKL administration in ovariectomized mice lacking CD8 T cells was also osteolytic, confirming that Tc(REG) mediate this bone anabolic effect. Our results show that although RANKL directly stimulates osteoclasts to resorb bone, it also controls the osteoclasts' ability to induce regulatory T cells, engaging an important negative feedback loop. In addition to the conceivable clinical relevance to treatment of osteoporosis, these observations have potential relevance to induction of tolerance and autoimmune diseases.
Collapse
Affiliation(s)
- Zachary S. Buchwald
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| | - Chang Yang
- Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis
| | - Suman Nellore
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| | - Elena V. Shashkova
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| | - Jennifer L. Davis
- Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis
| | - Anna Cline
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| | - Je Ko
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| | - Deborah V. Novack
- Division of Bone and Mineral Disease, Department of Medicine, Washington University in St. Louis
| | - Richard DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| | - Rajeev Aurora
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine
| |
Collapse
|
|
15
|
Clemente AM, Severini C, Castronovo G, Tanturli M, Perissi E, Cozzolino F, Torcia MG. Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes. Microbes Infect 2014; 16:778-87. [PMID: 25130316 DOI: 10.1016/j.micinf.2014.08.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 07/03/2014] [Accepted: 08/04/2014] [Indexed: 12/12/2022]
Abstract
Interference with transforming growth factor-β-mediated pathways helps several parasites to survive for long periods in immunocompetent hosts. Macrophages and dendritic cells infected by Toxoplasma, Leishmania and Plasmodium spp. produce large amounts of transforming growth factor-β and induce the differentiation of antigen-specific T-regulatory cells. Mechanisms not mediated by antigen-presentation could also account for the expansion of T-regulatory cells in parasitic diseases and they also might be mediated through transforming growth factor-β-receptor activated pathways. We explored the properties of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites, Trichinella spiralis muscle larvae to expand the pool of T-regulatory cells in a population of polyclonally activated T cells in the absence of accessory cells, and compared their effects to those induced by Plasmodium falciparum extracts. Similarly to P. falciparum, L. infantum extracts activate the latent soluble form of transforming growth factor-β and that bound to the membrane of activated T lymphocytes. The interaction of the active cytokine with transforming growth factor-β receptor induces Foxp3 expression by activated lymphocytes, favoring their conversion through the T-regulatory phenotype. Both Toxoplasma gondii and L. infantum extracts are able to induce transforming growth factor-β production by activated T cells in the absence of accessory cells.
Collapse
Affiliation(s)
- Ann Maria Clemente
- Department of Clinical and Experimental Medicine, University of Firenze, Largo Brambilla 3, I-50134, Firenze, Italy
| | - Carlo Severini
- Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161, Roma, Italy
| | - Giuseppe Castronovo
- Department of Biomedical, Experimental and Clinical Science, University of Firenze, Viale Giovan Battista Morgagni 50, I-50134, Firenze, Italy
| | - Michele Tanturli
- Department of Biomedical, Experimental and Clinical Science, University of Firenze, Viale Giovan Battista Morgagni 50, I-50134, Firenze, Italy
| | - Eloisa Perissi
- Department of Biomedical, Experimental and Clinical Science, University of Firenze, Viale Giovan Battista Morgagni 50, I-50134, Firenze, Italy
| | - Federico Cozzolino
- Department of Biomedical, Experimental and Clinical Science, University of Firenze, Viale Giovan Battista Morgagni 50, I-50134, Firenze, Italy
| | - Maria Gabriella Torcia
- Department of Clinical and Experimental Medicine, University of Firenze, Largo Brambilla 3, I-50134, Firenze, Italy.
| |
Collapse
|
|
16
|
Visperas A, Shen B, Min B. γδ T cells restrain extrathymic development of Foxp3+-inducible regulatory T cells via IFN-γ. Eur J Immunol 2014; 44:2448-56. [PMID: 24799116 DOI: 10.1002/eji.201344331] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 03/22/2014] [Accepted: 04/29/2014] [Indexed: 12/12/2022]
Abstract
Inducible Treg (iTreg) cells generated from Ag-stimulated naïve CD4(+) T cells in the periphery play an important role in regulating immune responses. TGF-β is a key cytokine that promotes this conversion process; however, how this process is regulated in vivo remains unclear. Here, we report that γδ T cells play a crucial role in controlling iTreg generation and suppressor function. Ag-induced iTreg generation was significantly enhanced in C57BL/6 mice in the absence of γδ T cells. Inhibition of iTreg conversion was mediated by IFN-γ produced by activated γδ T cells but not by activated CD4(+) T cells. BM chimera experiments further confirmed γδ-derived IFN-γ-dependent mechanism in regulating iTreg generation in vivo. Lastly, human peripheral blood γδ T cells also interfere with iTreg conversion via IFN-γ. Our results suggest a novel function of γδ T cells in limiting the generation of iTreg cells, potentially balancing immunity and tolerance.
Collapse
Affiliation(s)
- Anabelle Visperas
- Department of Immunology, Lerner Research Institute, Cleveland, OH, USA; Department of Molecular Medicine, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | | | | |
Collapse
|
|
17
|
MiRNome and transcriptome aided pathway analysis in human regulatory T cells. Genes Immun 2014; 15:303-12. [PMID: 24848933 DOI: 10.1038/gene.2014.20] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 03/24/2014] [Accepted: 03/27/2014] [Indexed: 12/15/2022]
Abstract
Owing to their manifold immune regulatory functions, regulatory T cells (Treg) have received tremendous interest as targets for therapeutic intervention of diverse immunological pathologies or cancer. Directed manipulation of Treg will only be achievable with extensive knowledge about the intrinsic programs that define their regulatory function. We simultaneously analyzed miR and mRNA transcript levels in resting and activated human Treg cells in comparison with non-regulatory conventional T cells (Tcon). Based on experimentally validated miR-target information, both transcript levels were integrated into a comprehensive pathway analysis. This strategy revealed characteristic signal transduction pathways involved in Treg biology such as T-cell receptor-, Toll-like receptor-, transforming growth factor-β-, JAK/STAT (Janus kinase/signal transducers and activators of transcription)- and mammalian target of rapamycin signaling, and allowed for the prediction of specific pathway activities on the basis of miR and mRNA transcript levels in a probabilistic manner. These data encourage new concepts for targeted control of Treg cell effector functions.
Collapse
|
|
18
|
Song P, Wang XW, Li HX, Li K, Liu L, Wei C, Jian Z, Yi XL, Li Q, Wang G, Li CY, Gao TW. Association between FOXP3 polymorphisms and vitiligo in a Han Chinese population. Br J Dermatol 2014; 169:571-8. [PMID: 23582052 DOI: 10.1111/bjd.12377] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND Vitiligo is an autoimmune chronic depigmentation disorder caused by melanocyte loss. Previous studies found that CD4(+)CD25(+) regulatory T-cell (Treg) dysfunction was involved in the pathogenesis of vitiligo and that gene polymorphisms in forkhead box P3 (FOXP3) - a master regulator of Treg development and function - were associated with susceptibility to some autoimmune disorders. Therefore, we hypothesized that functional polymorphisms of the FOXP3 gene might be associated with vitiligo via dysregulation of Treg cells. OBJECTIVES To evaluate whether FOXP3 polymorphisms are associated with vitiligo risk. MATERIAL AND METHODS In this hospital-based case-control study of 682 patients with vitiligo and 682 vitiligo-free age- and sex-matched controls, we genotyped three single nucleotide polymorphisms (SNPs) of the FOXP3 gene - rs2232365, rs3761548 and rs5902434 - by performing polymerase chain reaction with sequence-specific primers (PCR-SSP). RESULTS Significantly increased vitiligo risk was associated with the rs2232365 GG [odds ratio (OR) 1·68, 95% confidence interval (CI) 1·17-2·39, P = 0·004] and rs3761548 AA (OR 1·82, 95% CI 1·10-3·01, P = 0·033) genotypes compared with the rs2232365 AA and rs3761548 CC genotypes. On combined analysis of these three variant alleles, we found that individuals carrying 2-6 variant alleles had significantly increased vitiligo risk (OR 1·34, 95% CI 1·08-1·66). This risk was more pronounced in the following subgroups: age > 20 years, male sex, active vitiligo, nonsegmental vitiligo and other accompanying autoimmune diseases. CONCLUSIONS FOXP3 gene polymorphisms contributed to vitiligo risk in a Han Chinese population.
Collapse
Affiliation(s)
- P Song
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Changlexi Road No. 127, Xi'an, Shaanxi, 710032, China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Stumpf M, Zhou X, Chikuma S, Bluestone JA. Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function. Eur J Immunol 2014; 44:1737-46. [PMID: 24648182 DOI: 10.1002/eji.201343891] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 01/14/2014] [Accepted: 03/14/2014] [Indexed: 01/01/2023]
Abstract
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a major negative regulatory molecule for T-cell activation with a complex biology and function. CTLA-4 is known to regulate homeostatic lymphoproliferation as well as tolerance induction and has been proposed to be an important effector molecule by which Treg cells suppress immunity. The immunoregulatory properties of CTLA-4 are primarily mediated by competition with the costimulator CD28 for ligand binding but also by delivering negative signals to T cells through its cytoplasmic tail. In this study, we addressed the effect of directly mutating the amino acid residue, Tyrosine 201 (Tyr201), of the intracellular domain of CTLA-4 in situ and its implications in T-cell function in the context of autoimmunity. Therefore, a novel CTLA-4 knock-in mouse (Y201V KI) was generated, in which Tyr201 was replaced by a valine that could not be phosphorylated. Mice expressing the CTLA-4 mutant molecule were generally healthy and did not show signs of disruption of T-cell homeostasis under steady-state conditions seen in CTLA-4 deficient mice. However, T cells isolated from Y201V KI mice expressed higher levels of CTLA-4 on the cell surface and displayed a Th2-biased phenotype following TCR stimulation. Furthermore, Y201V KI mice developed exacerbated disease as compared to wild-type upon antigen-specific T-cell activation in an in vivo model of EAE. Importantly, the Y201V mutation resulted in impaired suppressive activity of Treg cells while T effector function remained intact. These data suggest that effects associated with and mediated through Tyr201 of CTLA-4s intracellular domain are critical for Treg-cell function.
Collapse
Affiliation(s)
- Melanie Stumpf
- Diabetes Center and the Department of Medicine, University of California, San Francisco, CA, USA; Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | | | | | | |
Collapse
|
|
20
|
Szylberg Ł, Bodnar M, Harasymczuk J, Marszalek A. Expression of FoxP3 protein plays a key role in thyroid tumors in children. Fetal Pediatr Pathol 2014; 33:84-91. [PMID: 24328999 DOI: 10.3109/15513815.2013.864347] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The expression of FoxP3 in tumor cells might play an important role in cancer progression. We evaluated the immunoexpression of FoxP3 in thyroid tumors in children. Studies revealed high nuclear FoxP3 expression in follicular adenoma, papillary carcinoma, follicular carcinoma and low in goiter. Malignant tumors and adenomas, revealed a statistically significant higher expression of FoxP3 compared with the thyroid goiter. High FoxP3 expression in malignant lesions compared with low expression in goiter, may be indirect evidence of its role in carcinogenesis. Revealed high expression of FoxP3 in benign tumor, may suggest a strong activation of oncogenic processes in this lesion.
Collapse
Affiliation(s)
- Łukasz Szylberg
- 1 Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Bydgoszcz, Poland
| | | | | | | |
Collapse
|
|
21
|
Shen Z, Chen L, Yang X, Zhao Y, Pier E, Zhang X, Yang X, Xiong Y. Downregulation of Ezh2 methyltransferase by FOXP3: New insight of FOXP3 into chromatin remodeling? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2013; 1833:2190-200. [DOI: 10.1016/j.bbamcr.2013.05.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 05/08/2013] [Accepted: 05/10/2013] [Indexed: 11/16/2022]
|
|
22
|
c-Jun N-terminal kinase (JNK)-phospho-c-JUN (ser63/73) pathway is essential for FOXP3 nuclear translocation in psoriasis. J Dermatol Sci 2013. [DOI: 10.1016/j.jdermsci.2012.10.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
23
|
Kornete M, Mason ES, Piccirillo CA. Immune Regulation in T1D and T2D: Prospective Role of Foxp3+ Treg Cells in Disease Pathogenesis and Treatment. Front Endocrinol (Lausanne) 2013; 4:76. [PMID: 23805128 PMCID: PMC3691561 DOI: 10.3389/fendo.2013.00076] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 06/08/2013] [Indexed: 12/18/2022] Open
Abstract
There is increasing evidence that dysregulated immune responses play key roles in the pathogenesis and complications of type 1 but also type 2 diabetes. Indeed, chronic inflammation and autoimmunity, which are salient features of type 1 diabetes, are now believed to actively contribute to the pathogenesis of type 2 diabetes. The accumulation of activated innate and adaptive immune cells in various metabolic tissues results in the release of inflammatory mediators, which promote insulin resistance and β-cell damage. Moreover, these dysregulated immune responses can also mutually influence the prevalence of both type 1 and 2 diabetes. In this review article, we discuss the central role of immune responses in the patho-physiology and complications of type 1 and 2 diabetes, and provide evidence that regulation of these responses, particularly through the action of regulatory T cells, may be a possible therapeutic avenue for the treatment of these disease and their respective complications.
Collapse
Affiliation(s)
- Mara Kornete
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
- FOCIS Center of Excellence, Research Institute of the McGill University Health Center, Montreal, QC, Canada
| | - Edward S. Mason
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
- FOCIS Center of Excellence, Research Institute of the McGill University Health Center, Montreal, QC, Canada
| | - Ciriaco A. Piccirillo
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
- FOCIS Center of Excellence, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Ciriaco A. Piccirillo, Research Institute of the McGill University Health Center, Montreal General Hospital, 1650 Cedar Avenue, Room L11.132, Montreal, QC H3G 1A4, Canada e-mail:
| |
Collapse
|
|
24
|
Chen L, Wu J, Pier E, Zhao Y, Shen Z. mTORC2-PKBα/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 Stability by chemokine CCL3 in psoriasis. J Invest Dermatol 2012; 133:418-28. [PMID: 23223135 DOI: 10.1038/jid.2012.333] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The connection between infections and acute guttate psoriasis (AGP) outbreaks/chronic plaque psoriasis (CPP) exacerbation has been known for years. Impaired function of FOXP3+Tregs in psoriasis has been identified. However, the mechanisms behind these two observations have not been fully interpreted. In the present study, we provide evidence to support chemokine CCL3 as one of the vital links between infections and FOXP3 stability in the psoriatic microenvironment. We found that serum CCL3, strongly induced by microorganism infections including streptococcus, was closely correlated with FOXP3 levels in CD4+CD25+T cells of patients with psoriasis. CCL3 manipulated FOXP3 stability in a concentration-dependent bidirectional manner. High-concentration CCL3 decreased FOXP3 stability by promoting FOXP3's degradation through K48-linkage ubiquitination. This degradation was mainly dependent on upregulation of Serine 473 phosphorylation of the PKBα/Akt1 isoform, and almost independent of mTORC1 (mammalian target of rapamycin complex 1) activity. On the other hand, low-concentration CCL3 could enhance FOXP3 stability by the maintenance of the PKC pathway and the restriction of the PKB/Akt pathway. We further demonstrated that enhancing FOXP3 stability by low-concentration CCL3 attributed, at least partly, to the prevention of cytoplasmic Sin1, a vital component of mTORC2, nuclear translocation. Our results suggest vital roles for CCL3-mTORC2-isoform PKB/Akt1 S473 phosphorylation axis in FOXP3+Tregs and the development of psoriasis.
Collapse
Affiliation(s)
- Ling Chen
- Department of Dermatology, Daping Hospital, Third Military Medical University, Chongqing, China
| | | | | | | | | |
Collapse
|
|
25
|
Elloumi HZ, Maharshak N, Rao KN, Kobayashi T, Ryu HS, Mühlbauer M, Li F, Jobin C, Plevy SE. A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis. PLoS One 2012; 7:e34172. [PMID: 22479554 PMCID: PMC3313977 DOI: 10.1371/journal.pone.0034172] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 02/28/2012] [Indexed: 01/08/2023] Open
Abstract
Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-γ induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10−/−) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10−/− mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases.
Collapse
Affiliation(s)
- Houda Z. Elloumi
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Nitsan Maharshak
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Kavitha N. Rao
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Taku Kobayashi
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Hyungjin S. Ryu
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Marcus Mühlbauer
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Fengling Li
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Christian Jobin
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Scott E. Plevy
- Center for Gastrointestinal Biology and Diseases, Departments of Medicine and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
- * E-mail:
| |
Collapse
|
|
26
|
Licciardi PV, Karagiannis TC. Regulation of immune responses by histone deacetylase inhibitors. ISRN HEMATOLOGY 2012; 2012:690901. [PMID: 22461998 PMCID: PMC3313568 DOI: 10.5402/2012/690901] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 01/10/2012] [Indexed: 01/01/2023]
Abstract
Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.
Collapse
Affiliation(s)
- Paul V Licciardi
- Allergy and Immune Disorders Group, Murdoch Childrens Research Institute, Melbourne, VIC 3052, Australia
| | | |
Collapse
|
|
27
|
Luo Y, Jiang W, Da Z, Wang B, Hu L, Zhang Y, An R, Yu H, Sun H, Tang K, Tang Z, Wang Y, Jing T, Zhu B. Subunit Vaccine Candidate AMM Down-Regulated the Regulatory T Cells and Enhanced the Protective Immunity of BCG on a Suitable Schedule. Scand J Immunol 2012; 75:293-300. [DOI: 10.1111/j.1365-3083.2011.02666.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
28
|
Adalid-Peralta L, Fragoso G, Fleury A, Sciutto E. Mechanisms underlying the induction of regulatory T cells and its relevance in the adaptive immune response in parasitic infections. Int J Biol Sci 2011; 7:1412-26. [PMID: 22110392 PMCID: PMC3221948 DOI: 10.7150/ijbs.7.1412] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 10/01/2011] [Indexed: 12/22/2022] Open
Abstract
To fulfill its function, the immune system must detect and interpret a wide variety of signals and adjust the magnitude, duration, and specific traits of each response during the complex host-parasite relationships in parasitic infections. Inflammation must be tightly regulated since uncontrolled inflammation may be as destructive as the triggering stimulus and leads to immune-mediated tissue injury. During recent years, increasing evidence points to regulatory T cells (Tregs) as key anti-inflammatory cells, critically involved in limiting the inflammatory response. Herein, we review the published information on the induction of Tregs and summarize the most recent findings on Treg generation in parasitic diseases.
Collapse
|
|
29
|
Clemente A, Caporale R, Sannella AR, Majori G, Severini C, Fadigati G, Cirelli D, Bonini P, Garaci E, Cozzolino F, Torcia MG. Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals. Cell Microbiol 2011; 13:1328-38. [DOI: 10.1111/j.1462-5822.2011.01622.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
|
|
30
|
Shen Z, Song Q, Chen L, Zhong B, Tang S, Hao F. Bidirectional immunoregulation of calcineurin inhibitor tacrolimus on FOXP3 transcription? Med Hypotheses 2011; 76:178-80. [PMID: 20937549 DOI: 10.1016/j.mehy.2010.09.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2010] [Revised: 08/19/2010] [Accepted: 09/06/2010] [Indexed: 12/01/2022]
Abstract
The imbalance between regulatory T cells (Treg) and effector T cells is important for maintaining of psoriasis vulgaris. FOXP3 is a master control transcription factor for the development and function of Tregs and is critical for transcriptional repression. Tacrolimus is effective in treatment of psoriasis vulgaris. Data show that tacrolimus has multiple impacts on FOXP3, but the exact pharmacological mechanism of tacrolimus on FOXP3 have yet to be elucidated. We herein suggest the bidirectional immunoregulation of tacrolimus on FOXP3. High concentration of tacrolimus renders the cooperation of NFAT with STAT6 and NF-κB to activate GATA3 transcription. On the contrary, low concentration of tacrolimus results in higher nucleus level of NFAT, which directly binds to FOXP3 enhancer and/or cooperates with Smad3 to activate FOXP3 transcription. Further studies using loss of function and over-expression methods are needed to determine the detailed molecules involved in this bidirectional immunoregulation of tacrolimus on FOXP3.
Collapse
Affiliation(s)
- Zhu Shen
- Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | | | | | | | | | | |
Collapse
|
|
31
|
Kandasamy M, Reilmann R, Winkler J, Bogdahn U, Aigner L. Transforming Growth Factor-Beta Signaling in the Neural Stem Cell Niche: A Therapeutic Target for Huntington's Disease. Neurol Res Int 2011; 2011:124256. [PMID: 21766020 PMCID: PMC3134994 DOI: 10.1155/2011/124256] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 02/19/2011] [Indexed: 12/31/2022] Open
Abstract
The neural stem cell niches possess the regenerative capacity to generate new functional neurons in the adult brain, suggesting the possibility of endogenous neuronal replacement after injury or disease. Huntington disease (HD) is a neurodegenerative disease and characterized by neuronal loss in the basal ganglia, leading to motor, cognitive, and psychological disabilities. Apparently, in order to make use of the neural stem cell niche as a therapeutic concept for repair strategies in HD, it is important to understand the cellular and molecular composition of the neural stem cell niche under such neurodegenerative conditions. This paper mainly discusses the current knowledge on the regulation of the hippocampal neural stem cell niche in the adult brain and by which mechanism it might be compromised in the case of HD.
Collapse
Affiliation(s)
- Mahesh Kandasamy
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria
| | - Ralf Reilmann
- Department of Neurology, University of Münster Medical School, 48129 Münster, Germany
| | - Jürgen Winkler
- Division of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany
| | - Ulrich Bogdahn
- Department of Neurology, University of Regensburg, D-93053 Regensburg, Germany
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria
| |
Collapse
|
|
32
|
Lei J, Hasegawa H, Matsumoto T, Yasukawa M. Peroxisome proliferator-activated receptor α and γ agonists together with TGF-β convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2010; 185:7186-98. [PMID: 21057085 DOI: 10.4049/jimmunol.1001437] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Human peripheral CD4(+)CD25(-) T cells can be induced to express Foxp3 when activated in vitro by TCR stimulation with TGF-β and IL-2. However, these TGF-β-induced Foxp3(+) regulatory T cells (iTregs) lack a regulatory phenotype. From libraries of nuclear receptor ligands and bioactive lipids, we screened three peroxisome proliferator-activated receptor (PPAR)α (bezafibrate, GW7647, and 5,8,11,14-eicosatetraynoic acid) and two PPARγ agonists (ciglitazone and 15-deoxy-Δ-(12,14)-PG J(2)) as molecules that increased Foxp3 expression in human iTregs significantly compared with that in DMSO-treated iTregs (control). These PPARα and PPARγ agonist-treated iTregs maintained a high level of Foxp3 expression and had suppressive properties. There were no significant differences in the suppressive properties of iTregs treated with the three PPARα and two PPARγ agonists, and all of the treated iTregs increased demethylation levels of the Foxp3 promoter and intronic conserved noncoding sequence 3 regions. Furthermore, PPARα and PPARγ agonists, together with TGF-β, more strongly inhibited the expression of all three DNA methyltransferases (DNMTs) (DNMT1, DNMT3a, and DNMT3b) in activated CD4(+) T cells. These results demonstrate that PPARα and PPARγ agonists together with TGF-β elicit Foxp3 DNA demethylation through potent downregulation of DNMTs and induce potent and stable Foxp3 expression, resulting in the generation of functional iTregs. Moreover, trichostatin A and retinoic acid enhanced the generation of iTregs synergistically with PPARα and PPARγ agonists.
Collapse
Affiliation(s)
- Jin Lei
- Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | | | | | | |
Collapse
|
|
33
|
Wang T, Monte MM, Huang W, Boudinot P, Martin SA, Secombes CJ. Identification of two FoxP3 genes in rainbow trout (Oncorhynchus mykiss) with differential induction patterns. Mol Immunol 2010; 47:2563-74. [DOI: 10.1016/j.molimm.2010.06.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 06/30/2010] [Indexed: 11/25/2022]
|
|
34
|
Casares N, Rudilla F, Arribillaga L, Llopiz D, Riezu-Boj JI, Lozano T, López-Sagaseta J, Guembe L, Sarobe P, Prieto J, Borrás-Cuesta F, Lasarte JJ. A Peptide Inhibitor of FOXP3 Impairs Regulatory T Cell Activity and Improves Vaccine Efficacy in Mice. THE JOURNAL OF IMMUNOLOGY 2010; 185:5150-9. [DOI: 10.4049/jimmunol.1001114] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
|
|
35
|
Kandasamy M, Couillard-Despres S, Raber KA, Stephan M, Lehner B, Winner B, Kohl Z, Rivera FJ, Nguyen HP, Riess O, Bogdahn U, Winkler J, von Hörsten S, Aigner L. Stem cell quiescence in the hippocampal neurogenic niche is associated with elevated transforming growth factor-beta signaling in an animal model of Huntington disease. J Neuropathol Exp Neurol 2010; 69:717-728. [PMID: 20535034 DOI: 10.1097/nen.0b013e3181e4f733] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cellular proliferation, differentiation, integration, and survival within the adult neural stem cell niche are altered under pathological conditions, but the molecular cues regulating the biology of this niche are mostly unknown. We examined the hippocampal neural stem cell niche in a transgenic rat model of Huntington disease. In this model, progressive cognitive deficits develop at the age of 9 months, suggesting possible hippocampal dysfunction. We found a disease-associated progressive decline in hippocampal progenitor cell proliferation accompanied by an expansion of the pool of 5-bromo-2-deoxyuridine label-retaining Sox-2-positive quiescent stem cells in the transgenic animals. Increments in quiescent stem cells occurred at the expense of cAMP-responsive element-binding protein-mediated neuronal differentiation and survival. Because elevated levels of transforming growth factor-beta1 (TGF-beta1) impair neural progenitor proliferation, we investigated hippocampal TGF-beta signaling and determined that TGF-beta1 induces the neural progenitors to exit the cell cycle. Although phospho-Smad2, an effector of TGF-beta signaling, is normally absent in subgranular stem cells, it accumulated progressively in Sox2/glial fibrillary acidic protein-expressing cells of the subgranular zone in the transgenic rats. These results indicate that alterations in neurogenesis in transgenic Huntington disease rats occur in successive phases that are associated with increasing TGF-beta signaling. Thus, TGF-beta1 signaling seems to be a crucial modulator of neurogenesis in Huntington disease and may represent a target for future therapy.
Collapse
Affiliation(s)
- Mahesh Kandasamy
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Padhan K, Varma R. Immunological synapse: a multi-protein signalling cellular apparatus for controlling gene expression. Immunology 2010; 129:322-8. [PMID: 20409153 DOI: 10.1111/j.1365-2567.2009.03241.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The interaction of T cells with antigen-presenting cells is the hallmark of adaptive immunity. In vitro studies have described the formation of an immunological synapse between these cells, and intra-vital imaging has described in great detail the dynamics of these interactions. The immunological synapse has become a paradigm to study signals exchanged between the two cells. A wealth of information has been amassed regarding the localization of signalling molecules, their kinetics and the transcription factors they activate. We continue to discover mechanisms that cause receptors and signalling molecules to compartmentalize in the cell; however, the emerging challenge lies in understanding how the immunological synapse contributes to differentiation. Here, we review some of the transcription factors activated downstream of T-cell receptor signalling and discuss mechanisms by which antigen dose and affinity may influence differentiation. Antigen affinity might change the kind of transcription factors that are activated whereas antigen dose is likely to influence the temporal dynamics of the transcription factors. The immunological synapse is therefore likely to influence differentiation by modulating the trafficking of transcription factors and by promoting asymmetric cell division, an emerging concept.
Collapse
Affiliation(s)
- Kartika Padhan
- Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | | |
Collapse
|