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Chang E, Cavallo K, Behar SM. CD4 T cell dysfunction is associated with bacterial recrudescence during chronic tuberculosis. Nat Commun 2025; 16:2636. [PMID: 40097414 PMCID: PMC11914476 DOI: 10.1038/s41467-025-57819-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
While most people contain Mycobacterium tuberculosis infection, some individuals develop active disease, usually within two years of infection. Why immunity fails after initially controlling infection is unknown. C57BL/6 mice control Mycobacterium tuberculosis for up to a year but ultimately succumb to disease. We hypothesize that the development of CD4 T cell dysfunction permits bacterial recrudescence. We developed a reductionist model to assess antigen-specific T cells during chronic infection and found evidence of CD4 T cell senescence and exhaustion. In C57BL/6 mice, CD4 T cells upregulate coinhibitory receptors and lose effector cytokine production. Single cell RNAseq shows that only a small number of CD4 T cells in the lungs of chronically infected mice are polyfunctional. While the origin and causal relationship between T-cell dysfunction and recrudescence remains uncertain, we propose T cell dysfunction leads to a feed-forward loop that causes increased bacillary numbers, greater T cell dysfunction, and progressive disease.
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Affiliation(s)
- Evelyn Chang
- Immunology and Microbiology Program, Morningside Graduate School of Biomedical Sciences, Worcester, MA, USA
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kelly Cavallo
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Samuel M Behar
- Immunology and Microbiology Program, Morningside Graduate School of Biomedical Sciences, Worcester, MA, USA.
- Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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2
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Chang E, Cavallo K, Behar SM. CD4 T cell dysfunction is associated with bacterial recrudescence during chronic tuberculosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.634376. [PMID: 39896548 PMCID: PMC11785196 DOI: 10.1101/2025.01.22.634376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
While most people contain Mycobacterium tuberculosis infection, some individuals develop active disease, usually within two years of infection. Why immunity fails after initially controlling infection is unknown. C57BL/6 mice control Mycobacterium tuberculosis for up to a year but ultimately succumb to disease. We hypothesize that the development of CD4 T cell dysfunction permits bacterial recrudescence. We developed a reductionist model to assess antigen-specific T cells during chronic infection and found evidence of CD4 T cell senescence and exhaustion. In C57BL/6 mice, CD4 T cells upregulate coinhibitory receptors and lose effector cytokine production. Single cell RNAseq shows that only a small number of CD4 T cells in the lungs of chronically infected mice are polyfunctional. While the origin and causal relationship between T-cell dysfunction and recrudescence remains uncertain, we propose T cell dysfunction leads to a feed-forward loop that causes increased bacillary numbers, greater T cell dysfunction, and progressive disease.
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Affiliation(s)
- Evelyn Chang
- Immunology and Microbiology Program, Graduate School of Biomedical Science, Worcester, Massachusetts, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Kelly Cavallo
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Samuel M. Behar
- Immunology and Microbiology Program, Graduate School of Biomedical Science, Worcester, Massachusetts, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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3
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Meade RK, Smith CM. Immunological roads diverged: mapping tuberculosis outcomes in mice. Trends Microbiol 2025; 33:15-33. [PMID: 39034171 DOI: 10.1016/j.tim.2024.06.007] [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: 05/06/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/23/2024]
Abstract
The journey from phenotypic observation to causal genetic mechanism is a long and challenging road. For pathogens like Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), host-pathogen coevolution has spanned millennia, costing millions of human lives. Mammalian models can systematically recapitulate host genetic variation, producing a spectrum of disease outcomes. Leveraging genome sequences and deep phenotyping data from infected mouse genetic reference populations (GRPs), quantitative trait locus (QTL) mapping approaches have successfully identified host genomic regions associated with TB phenotypes. Here, we review the ongoing optimization of QTL mapping study design alongside advances in mouse GRPs. These next-generation resources and approaches have enabled identification of novel host-pathogen interactions governing one of the most prevalent infectious diseases in the world today.
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Affiliation(s)
- Rachel K Meade
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA; University Program in Genetics and Genomics, Duke University, Durham, NC, USA
| | - Clare M Smith
- Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA; University Program in Genetics and Genomics, Duke University, Durham, NC, USA.
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4
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Williams CG, Moreira ML, Asatsuma T, Lee HJ, Li S, Barrera I, Murray E, Soon MSF, Engel JA, Khoury DS, Le S, Wanrooy BJ, Schienstock D, Alexandre YO, Skinner OP, Joseph R, Beattie L, Mueller SN, Chen F, Haque A. Plasmodium infection induces phenotypic, clonal, and spatial diversity among differentiating CD4 + T cells. Cell Rep 2024; 43:114317. [PMID: 38848213 DOI: 10.1016/j.celrep.2024.114317] [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: 12/10/2023] [Revised: 04/21/2024] [Accepted: 05/20/2024] [Indexed: 06/09/2024] Open
Abstract
Naive CD4+ T cells must differentiate in order to orchestrate immunity to Plasmodium, yet understanding of their emerging phenotypes, clonality, spatial distributions, and cellular interactions remains incomplete. Here, we observe that splenic polyclonal CD4+ T cells differentiate toward T helper 1 (Th1) and T follicular helper (Tfh)-like states and exhibit rarer phenotypes not elicited among T cell receptor (TCR) transgenic counterparts. TCR clones present at higher frequencies exhibit Th1 skewing, suggesting that variation in major histocompatibility complex class II (MHC-II) interaction influences proliferation and Th1 differentiation. To characterize CD4+ T cell interactions, we map splenic microarchitecture, cellular locations, and molecular interactions using spatial transcriptomics at near single-cell resolution. Tfh-like cells co-locate with stromal cells in B cell follicles, while Th1 cells in red pulp co-locate with activated monocytes expressing multiple chemokines and MHC-II. Spatial mapping of individual transcriptomes suggests that proximity to chemokine-expressing monocytes correlates with stronger effector phenotypes in Th1 cells. Finally, CRISPR-Cas9 gene disruption reveals a role for CCR5 in promoting clonal expansion and Th1 differentiation. A database of cellular locations and interactions is presented: https://haquelab.mdhs.unimelb.edu.au/spatial_gui/.
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Affiliation(s)
- Cameron G Williams
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Marcela L Moreira
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Takahiro Asatsuma
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Hyun Jae Lee
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Shihan Li
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Irving Barrera
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Evan Murray
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Megan S F Soon
- QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia
| | - Jessica A Engel
- QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia
| | - David S Khoury
- Kirby Institute, University of New South Wales, Kensington, NSW 2052, Australia
| | - Shirley Le
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Brooke J Wanrooy
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Dominick Schienstock
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Yannick O Alexandre
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Oliver P Skinner
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Rainon Joseph
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Lynette Beattie
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia
| | - Fei Chen
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Ashraful Haque
- Department of Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Parkville, VIC 3000, Australia.
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Qin Y, Wang Q, Shi J. Immune checkpoint modulating T cells and NK cells response to Mycobacterium tuberculosis infection. Microbiol Res 2023; 273:127393. [PMID: 37182283 DOI: 10.1016/j.micres.2023.127393] [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: 11/12/2022] [Revised: 04/07/2023] [Accepted: 04/22/2023] [Indexed: 05/16/2023]
Abstract
Many subversive mechanisms promote the occurrence and development of chronic infectious diseases and cancer, among which the down-regulated expression of immune-activating receptors and the enhanced expression of immune-inhibitory receptors accelerate the occurrence and progression of the disease. Recently, the use of immune checkpoint inhibitors has shown remarkable efficacy in the treatment of tumors in multiple organs. However, the expression of immune checkpoint molecules on natural killer (NK) cells by Mycobacterium tuberculosis (Mtb) infection and its impact on NK cell effector functions have been poorly studied. In this review, we focus on what is currently known about the expression of various immune checkpoints in NK cells following Mtb infection and how it alters NK cell-mediated host cytotoxicity and cytokine secretion. Unraveling the function of NK cells after the infection of host cells by Mtb is crucial for a comprehensive understanding of the innate immune mechanism of NK cells involved in tuberculosis and the evaluation of the efficacy of immunotherapies using immune checkpoint inhibitors to treat tuberculosis. In view of some similarities in the immune characteristics of T cells and NK cells, we reviewed the molecular mechanism of the interaction between T cells and Mtb, which can help us to further understand and explore the specific interaction mechanism between NK cells and Mtb.
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Affiliation(s)
- Yongwei Qin
- Department of Pathogen Biology, Medical College, Nantong University, No. 19 Qixiu Road, Nantong 226001, China.
| | - Qinglan Wang
- Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Jiahai Shi
- Department of Thoracic Surgery, Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, and Research Institution of Translational Medicine in Cardiothoracic Diseases in Affiliated Hospital of Nantong University, No. 20 Xisi Road, Nantong 226001, China
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Wakchoure P, Momin K, Khan AA. Pathogenesis of Human Immunodeficiency Virus and Mycobacterium tuberculosis Infection as Revealed by Transcriptome and Interactome Data. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:15-23. [PMID: 36648422 DOI: 10.1089/omi.2022.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Tuberculosis (TB) among patients with human immunodeficiency virus (HIV) is a major global health burden and contributes to a high mortality rate due to HIV-mediated immunosuppression and subsequent susceptibility to TB. It is imperative to understand the pathogenesis of the association between HIV and TB for therapeutic innovation and preventive medicine. In the present study, we employed transcriptomic and bioinformatic analyses of differential gene expression data obtained from Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information. The expression data of Mycobacterium tuberculosis-infected macrophages and blood samples from TB patients (GSE54992, GSE52819, and GSE19435) and blood samples from HIV patients (GSE30310) were accessed for identification of differentially expressed genes (DEGs). Data from 20 healthy subjects and 19 patients with TB and 16 healthy subjects and 16 patients with HIV were analyzed. We report here the DEGs shared by HIV and TB infection. Moreover, HIV and TB host-pathogen interaction data were collected from BIOGRID, v 4.4.210, for identifying significantly modulated genes' targets and their interactions with the host. Host targets, including PLSCR1 (phospholipid scramblase 1), STAT1 (signal transducer and activator of transcription-1 alpha/beta), FBXO6 (F-box only protein 6), ITGAL (integrin alpha-L), and APP (amyloid beta precursor protein), are commonly modulated in both diseases. The function of these targets was screened from and reconciled with the literature to understand their role in the pathogenesis of HIV and TB. Overall, the study results suggest that these targets may potentially be important contributors to the pathogenesis of this comorbidity. Further experimental work is needed for evaluating these new observations, with a view to future therapeutic innovation for patients with HIV and TB.
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Affiliation(s)
- Pooja Wakchoure
- Division of Microbiology, ICMR-National AIDS Research Institute, Pune, India
| | - Khizra Momin
- Division of Microbiology, ICMR-National AIDS Research Institute, Pune, India
| | - Abdul Arif Khan
- Division of Microbiology, ICMR-National AIDS Research Institute, Pune, India
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Suksawat Y, Pacharn P, Siripipattanamongkol N, Boonyawat B. Three novel homozygous ITGB2 mutations among two patients with leukocyte adhesion defect type-1: Two case reports. World J Clin Pediatr 2022; 11:429-436. [PMID: 36185095 PMCID: PMC9516493 DOI: 10.5409/wjcp.v11.i5.429] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/10/2022] [Accepted: 08/22/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A leukocyte adhesion defect (LAD) is a rare primary immunodeficiency disorder. LAD type 1 (LAD-1) is the most common, which is caused by ITGB2 mutation resulting in dysfunction of β2 integrin, which impairs leukocyte adherence to the endothelium.
CASE SUMMARY The first two cases of LAD-1 in Thailand presented with recurrent omphalitis, soft tissue infection, marked leukocytosis, and neutrophilia. One patient experienced delayed umbilical cord separation. Mutation analysis was performed by direct DNA sequencing of the ITGB2 gene. The results revealed two novel homozygous missense mutations, c.920C>T (p.Leu307Pro) in exon 8 and c.758G>A (p.Arg253His) in exon 7, and one novel homozygous nonsense mutation, c.262C>T (p.Gln88Ter) in exon 4, in the genomic DNA of the first and second patients, respectively. Heterozygous mutations were identified in the parents of both patients, suggesting a carrier status. The patients were administered intravenous antibiotics for infections with good clinical responses. Hematopoietic stem cell transplantation could not be performed due to the unavailability of matched donors. However, a significant decline in infections was observed after antibiotic prophylaxis. Several follow-up visits were conducted for both patients. They are currently 6 years old.
CONCLUSION Molecular analysis is essential for definitive diagnosis, early treatment implementation, and prevention of LAD-1 in future pregnancy.
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Affiliation(s)
- Yiwa Suksawat
- Division of Allergy and Immunology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok 10400, Thailand
| | - Punchama Pacharn
- Division of Allergy and Immunology, Department of Pediatrics, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nunthana Siripipattanamongkol
- Division of Allergy and Immunology, Department of Pediatrics, Chiangrai Prachanukroh Regional Hospital, Chiangrai 57000, Thailand
| | - Boonchai Boonyawat
- Division of Medical Genetics, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok 10400, Thailand
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Bednarczyk M, Bolduan V, Haist M, Stege H, Hieber C, Johann L, Schelmbauer C, Blanfeld M, Karram K, Schunke J, Klaus T, Tubbe I, Montermann E, Röhrig N, Hartmann M, Schlosser J, Bopp T, Clausen BE, Waisman A, Bros M, Grabbe S. β2 Integrins on Dendritic Cells Modulate Cytokine Signaling and Inflammation-Associated Gene Expression, and Are Required for Induction of Autoimmune Encephalomyelitis. Cells 2022; 11:cells11142188. [PMID: 35883631 PMCID: PMC9322999 DOI: 10.3390/cells11142188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 01/27/2023] Open
Abstract
Heterodimeric β2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common β2 (CD18) subunit, which hampers the analysis of the cell type-specific role of β2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of β2 integrins, specifically in dendritic cells (DCs). Stimulated β2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired expression of suppressor of cytokine signaling (SOCS) 2–6 as assessed in bone marrow-derived (BM) DCs. Paradoxically, these BMDCs also showed the attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific β2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell populations (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove to be a valuable tool to study the leukocyte-specific functions of β2 integrins in vivo.
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Affiliation(s)
- Monika Bednarczyk
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Vanessa Bolduan
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Maximilian Haist
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Henner Stege
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Christoph Hieber
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Lisa Johann
- Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (L.J.); (C.S.); (M.B.); (K.K.); (B.E.C.); (A.W.)
| | - Carsten Schelmbauer
- Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (L.J.); (C.S.); (M.B.); (K.K.); (B.E.C.); (A.W.)
| | - Michaela Blanfeld
- Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (L.J.); (C.S.); (M.B.); (K.K.); (B.E.C.); (A.W.)
| | - Khalad Karram
- Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (L.J.); (C.S.); (M.B.); (K.K.); (B.E.C.); (A.W.)
- Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
| | - Jenny Schunke
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Tanja Klaus
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Ingrid Tubbe
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Evelyn Montermann
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Nadine Röhrig
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Maike Hartmann
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Jana Schlosser
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
| | - Tobias Bopp
- Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
- Institute of Immunology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Björn E Clausen
- Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (L.J.); (C.S.); (M.B.); (K.K.); (B.E.C.); (A.W.)
- Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (L.J.); (C.S.); (M.B.); (K.K.); (B.E.C.); (A.W.)
- Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
| | - Matthias Bros
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
- Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
| | - Stephan Grabbe
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (V.B.); (M.H.); (H.S.); (C.H.); (J.S.); (T.K.); (I.T.); (E.M.); (N.R.); (M.H.); (J.S.); (M.B.)
- Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
- Correspondence: ; Tel.: +49-61-3117-4412
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Dubey N, Khan MZ, Kumar S, Sharma A, Das L, Bhaduri A, Singh Y, Nandicoori VK. Mycobacterium tuberculosis PPiA interacts with host integrin receptor to exacerbate disease progression. J Infect Dis 2021; 224:1383-1393. [PMID: 33580239 DOI: 10.1093/infdis/jiab081] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 02/05/2021] [Indexed: 11/14/2022] Open
Abstract
Attenuated intracellular survival of Mycobacterium tuberculosis (Mtb) secretory gene mutants exemplifies their role as virulence factors. Mtb peptidyl prolyl isomerase A (PPiA) assists in protein folding through cis/trans isomerization of prolyl bonds. Here, we show that PPiA abets Mtb survival and aids in the disease progression by exploiting host-associated factors. While the deletion of PPiA has no discernable effect on the bacillary survival in a murine infection model, it compromises the formation of granuloma-like lesions and promotes host cell death through ferroptosis. Overexpression of PPiA enhances the bacillary load and exacerbates pathology in mice lungs. Importantly, PPiA interacts with the integrin α5β1 receptor through a conserved surface-exposed RGD motif. The secretion of PPiA as well as interaction with integrin contributes to the disease progression by upregulating multiple host matrix metalloproteinases. Collectively, we identified a novel non-chaperone role of PPiA that is critical in facilitating host-pathogen interaction ensuing disease progression.
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Affiliation(s)
- Neha Dubey
- Department of Zoology, University of Delhi, Mall Road, Delhi, India.,Current Department of Molecular Microbiology, WUSTL, St. Louis, USA
| | - Mehak Zahoor Khan
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Suresh Kumar
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India
| | - Aditya Sharma
- Department of Zoology, University of Delhi, Mall Road, Delhi, India.,Current Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, Texas, USA
| | - Lahari Das
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, India.,Current Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, Texas, USA
| | - Asani Bhaduri
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, India.,Current Cluster Innovation Center, University of Delhi, Mall Road, Delhi, India
| | - Yogendra Singh
- Department of Zoology, University of Delhi, Mall Road, Delhi, India
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10
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Perro M, Iannacone M, von Andrian UH, Peixoto A. Role of LFA-1 integrin in the control of a lymphocytic choriomeningitis virus (LCMV) infection. Virulence 2020; 11:1640-1655. [PMID: 33251934 PMCID: PMC7714442 DOI: 10.1080/21505594.2020.1845506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Leukocyte function-associated antigen 1 (LFA-1) is the most widely expressed member of the β2 integrin family of cell-cell adhesion molecules. Although LFA-1 is thought to regulate multiple aspects of T cell immunity, its role in the response of CD8+ T cells to viral infections remains unclear. Indeed, compelling clinical evidence shows that loss of LFA-1 function predisposes to infection in humans but animal models show limited to no susceptibility to infection. Here, we addressed this conundrum in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV), where CD8+ T cells are necessary and sufficient to confer protection. To this end, we followed the fate and function of wild-type and LFA-1 deficient virus-specific CD8+ T cells and assessed the effect of blocking anti-LFA-1 monoclonal antibody in the outcome of infection. Our analysis of viral clearance and T cell responses using transcriptome profiling reveals a role for LFA-1 as a gatekeeper of effector T cell survival and dysfunction that when defective can predispose to LCMV infection.
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Affiliation(s)
- Mario Perro
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
| | - Matteo Iannacone
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
| | - Ulrich H von Andrian
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
| | - Antonio Peixoto
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
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11
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Abstract
Sepsis remains medically challenging, with high morbidity and mortality. A novel intervention is urgently needed in the absence of specific, targeted therapy. Neutrophils act as double-edged swords in sepsis; they can help to eradicate microbes, but they also contribute to tissue injury. β2 integrins are critical adhesion molecules that regulate a number of neutrophil functions. β2 integrins consist of four members, namely, αLβ2, αMβ2, αXβ2, and αDβ2. Here, we review the role of each β2 integrin in neutrophils and sepsis and consider future direction for therapeutic intervention.
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12
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Bednarczyk M, Stege H, Grabbe S, Bros M. β2 Integrins-Multi-Functional Leukocyte Receptors in Health and Disease. Int J Mol Sci 2020; 21:E1402. [PMID: 32092981 PMCID: PMC7073085 DOI: 10.3390/ijms21041402] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/25/2022] Open
Abstract
β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development.
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Affiliation(s)
| | | | | | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.B.); (H.S.); (S.G.)
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13
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A Loss-of-Function Mutation in the Integrin Alpha L ( Itgal) Gene Contributes to Susceptibility to Salmonella enterica Serovar Typhimurium Infection in Collaborative Cross Strain CC042. Infect Immun 2019; 88:IAI.00656-19. [PMID: 31636138 DOI: 10.1128/iai.00656-19] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 10/05/2019] [Indexed: 12/18/2022] Open
Abstract
Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.
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14
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Abstract
The variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible to M. tuberculosis infection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in the Itgal gene, which is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource. Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis
infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-γ) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL that were associated with bacterial burden, IFN-γ production following infection, and an IFN-γ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and that these T cells failed to express the integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in the Itgal gene, which encodes CD11a and is found within the Tip2 interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. The ItgalCC042 genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042 mice. The combined effect of functionally distinct Tip variants likely explains the profound susceptibility of CC042 mice and highlights the multigenic nature of tuberculosis control in the Collaborative Cross.
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15
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Regulation of cell adhesion: a collaborative effort of integrins, their ligands, cytoplasmic actors, and phosphorylation. Q Rev Biophys 2019; 52:e10. [PMID: 31709962 DOI: 10.1017/s0033583519000088] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Integrins are large heterodimeric type 1 membrane proteins expressed in all nucleated mammalian cells. Eighteen α-chains and eight β-chains can combine to form 24 different integrins. They are cell adhesion proteins, which bind to a large variety of cellular and extracellular ligands. Integrins are required for cell migration, hemostasis, translocation of cells out from the blood stream and further movement into tissues, but also for the immune response and tissue morphogenesis. Importantly, integrins are not usually active as such, but need activation to become adhesive. Integrins are activated by outside-in activation through integrin ligand binding, or by inside-out activation through intracellular signaling. An important question is how integrin activity is regulated, and this topic has recently drawn much attention. Changes in integrin affinity for ligand binding are due to allosteric structural alterations, but equally important are avidity changes due to integrin clustering in the plane of the plasma membrane. Recent studies have partially solved how integrin cell surface structures change during activation. The integrin cytoplasmic domains are relatively short, but by interacting with a variety of cytoplasmic proteins in a regulated manner, the integrins acquire a number of properties important not only for cell adhesion and movement, but also for cellular signaling. Recent work has shown that specific integrin phosphorylations play pivotal roles in the regulation of integrin activity. Our purpose in this review is to integrate the present knowledge to enable an understanding of how cell adhesion is dynamically regulated.
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16
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T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming. Mucosal Immunol 2019; 12:1220-1230. [PMID: 31278374 PMCID: PMC6717559 DOI: 10.1038/s41385-019-0183-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/09/2019] [Accepted: 06/04/2019] [Indexed: 02/04/2023]
Abstract
Although clearance of many intracellular pathogens requires T-bet-dependent CD4 T cell programming, the extent to which T-bet is needed to direct protective CD4 responses against influenza is not known. Here, we characterize wild-type and T-bet-deficient CD4 cells during murine influenza infection. Surprisingly, although T-bet expression has broad impacts on cytokine production by virus-specific CD4 cells, the protective efficacy of T-bet-deficient effector cells is only marginally reduced. This reduction is due to lower CXCR3 expression, leading to suboptimal accumulation of activated T-bet-deficient cells in the infected lung. However, T-bet-deficient cells outcompete wild-type cells to form lung-resident and circulating memory populations following viral clearance, and primed T-bet-deficient mice efficiently clear supralethal heterosubtypic influenza challenges even when depleted of CD8 T cells. These results are relevant to the identification of more incisive correlates of protective T cells and for vaccines that aim to induce durable cellular immunity against influenza.
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17
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Abstract
ISG15 is a ubiquitin-like protein (Ubl) that is expressed in response to Type 1 Interferon (IFN-α/β) signaling. Remarkably, ISG15 has three distinct biochemical activities involved in innate immune responses to viral and/or microbial infections. The canonical function of ISG15 is as a posttranslational modifier, and protein ISGylation has been demonstrated to be antiviral. A second intracellular function, independent of conjugation activity, is attenuation of IFN-α/β signaling at the interferon receptor, which appears to be important for terminating IFN responses. The third function of ISG15, and the focus of this chapter, is as an extracellular signaling molecule that promotes the secretion of Type 2 Interferon (IFN-γ) by Natural Killer (NK) cells. This function is important for control of microbial infections, including mycobacterial infections. Here, we describe methods for purification of ISG15, preparation, and culture of primary peripheral blood mononuclear cells (PBMCs) and NK-92 cells, assays for IL-12- and ISG15-dependent cytokine (IFN-γ and IL-10) secretion, and assays for initial intracellular signaling events triggered by extracellular ISG15.
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18
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Abstract
Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.
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19
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Lindenstrøm T, Moguche A, Damborg M, Agger EM, Urdahl K, Andersen P. T Cells Primed by Live Mycobacteria Versus a Tuberculosis Subunit Vaccine Exhibit Distinct Functional Properties. EBioMedicine 2017; 27:27-39. [PMID: 29249639 PMCID: PMC5828549 DOI: 10.1016/j.ebiom.2017.12.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 11/22/2017] [Accepted: 12/05/2017] [Indexed: 01/10/2023] Open
Abstract
Despite inducing strong T cell responses, Mycobacterium tuberculosis (Mtb) infection fails to elicit protective immune memory. As such latently infected or successfully treated Tuberculosis (TB) patients are not protected against recurrent disease. Here, using a mouse model of aerosol Mtb infection, we show that memory immunity to H56/CAF01 subunit vaccination conferred sustained protection in contrast to the transient natural immunity conferred by Mtb infection. Loss of protection to re-infection in natural Mtb memory was temporally linked to an accelerated differentiation of ESAT-6- and to a lesser extent, Ag85B-specific CD4 T cells in both the lung parenchyma and vasculature. This phenotype was characterized by high KLRG1 expression and low, dual production of IFN-γ and TNF. In contrast, H56/CAF01 vaccination elicited cells that expressed low levels of KLRG1 with copious expression of IL-2 and IL-17A. Co-adoptive transfer studies revealed that H56/CAF01 induced memory CD4 T cells efficiently homed into the lung parenchyma of mice chronically infected with Mtb. In comparison, natural Mtb infection- and BCG vaccine-induced memory CD4 T cells exhibited a poor ability to home into the lung parenchyma. These studies suggest that impaired lung migratory capacity is an inherent trait of the terminally differentiated memory responses primed by mycobacteria/mycobacterial vectors.
Differentiation state of M. tuberculosis (Mtb)-specific CD4 memory T cells differ depending on their initial priming Live mycobacteria prime fully differentiated CD4 memory T cells with lower lung homing capacity than subunit vaccination Lung parenchymal Mtb memory CD4 T cells produce fewer & less cytokines, express more KLRG1 and cannot sustain protection People latently infected with M. tuberculosis or successfully treated for Tuberculosis are not protected against recurrent disease, even in the presence of strong T cell responses. Here, using a well-established mouse model, we show that in contrast to subunit vaccination, live mycobacteria prime CD4 T cells that are highly differentiated, have an inferior lung homing capacity and show impaired function once in the parenchyma leading to lack of sustained protection against challenge. This indicates a central shortcoming of natural immunity that needs to be addressed in order to develop improved vaccines against TB.
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Affiliation(s)
- Thomas Lindenstrøm
- Department of Infectious Disease Immunology, Statens Serum Institut, Denmark.
| | | | - Mie Damborg
- Department of Infectious Disease Immunology, Statens Serum Institut, Denmark
| | - Else Marie Agger
- Department of Infectious Disease Immunology, Statens Serum Institut, Denmark
| | - Kevin Urdahl
- Center for Infectious Disease Research, Seattle, USA
| | - Peter Andersen
- Department of Infectious Disease Immunology, Statens Serum Institut, Denmark
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20
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Swaim CD, Scott AF, Canadeo LA, Huibregtse JM. Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Mol Cell 2017; 68:581-590.e5. [PMID: 29100055 DOI: 10.1016/j.molcel.2017.10.003] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/31/2017] [Accepted: 10/03/2017] [Indexed: 12/30/2022]
Abstract
ISG15 is a ubiquitin-like protein that functions in innate immunity both as an intracellular protein modifier and as an extracellular signaling molecule that stimulates IFN-γ secretion. The extracellular function, important for resistance to mycobacterial disease, has remained biochemically uncharacterized. We have established an NK-92 cell-based assay for IFN-γ release, identified residues critical for ISG15 signaling, and identified the cell surface receptor as LFA-1 (CD11a/CD18; αLβ2 integrin). LFA-1 inhibition blocked IFN-γ secretion, splenocytes from CD11a-/- mice did not respond to ISG15, and ISG15 bound directly to the αI domain of CD11a in vitro. ISG15 also enhanced secretion of IL-10, indicating a broader role for ISG15 in cytokine signaling. ISG15 engagement of LFA-1 led to the activation of SRC family kinases (SFKs) and SFK inhibition blocked cytokine secretion. These findings establish the molecular basis of the extracellular function of ISG15 and the initial outside-in signaling events that drive ISG15-dependent cytokine secretion.
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Affiliation(s)
- Caleb D Swaim
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
| | - Ariella F Scott
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
| | - Larissa A Canadeo
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
| | - Jon M Huibregtse
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
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21
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Le Nours J, Shahine A, Gras S. Molecular features of lipid-based antigen presentation by group 1 CD1 molecules. Semin Cell Dev Biol 2017; 84:48-57. [PMID: 29113870 DOI: 10.1016/j.semcdb.2017.11.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 09/12/2017] [Accepted: 11/02/2017] [Indexed: 11/18/2022]
Abstract
Lipids are now widely considered to play a variety of important roles in T-cell mediated immunity, including serving as antigens. Lipid-based antigens are presented by a specialised group of glycoproteins termed CD1. In humans, three classes of CD1 molecules exist: group 1 (CD1a, CD1b, CD1c), group 2 (CD1d), and group 3 (CD1e). While CD1d-mediated T-cell immunity has been extensively investigated, we have only recently gained insights into the structure and function of group 1 CD1 molecules. Structural studies have revealed how lipid-based antigens are presented by group 1 CD1 molecules, as well as shedding light on the molecular requirements for T-cell recognition. Here, we provide an overview of our current understanding of lipid presentation by group 1 CD1 molecules in humans and their recognition by T-cells, as well as examining the potential differences in lipid presentation that may occur across different species.
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Affiliation(s)
- Jérôme Le Nours
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
| | - Adam Shahine
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Stephanie Gras
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
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22
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Capece T, Walling BL, Lim K, Kim KD, Bae S, Chung HL, Topham DJ, Kim M. A novel intracellular pool of LFA-1 is critical for asymmetric CD8 + T cell activation and differentiation. J Cell Biol 2017; 216:3817-3829. [PMID: 28954823 PMCID: PMC5674876 DOI: 10.1083/jcb.201609072] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/13/2017] [Accepted: 07/11/2017] [Indexed: 11/22/2022] Open
Abstract
The integrin lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) is a key T cell adhesion receptor that mediates stable interactions with antigen-presenting cell (APC), as well as chemokine-mediated migration. Using our newly generated CD11a-mYFP knock-in mice, we discovered that naive CD8+ T cells reserve a significant intracellular pool of LFA-1 in the uropod during migration. Intracellular LFA-1 quickly translocated to the cell surface with antigenic stimulus. Importantly, the redistribution of intracellular LFA-1 at the contact with APC was maintained during cell division and led to an unequal inheritance of LFA-1 in divided T cells. The daughter CD8+ T cells with disparate LFA-1 expression showed different patterns of migration on ICAM-1, APC interactions, and tissue retention, as well as altered effector functions. In addition, we identified Rab27 as an important regulator of the intracellular LFA-1 translocation. Collectively, our data demonstrate that an intracellular pool of LFA-1 in naive CD8+ T cells plays a key role in T cell activation and differentiation.
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Affiliation(s)
- Tara Capece
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Brandon L Walling
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Kihong Lim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Kyun-Do Kim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Seyeon Bae
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Hung-Li Chung
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - David J Topham
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Minsoo Kim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
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23
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Abstract
A CRISPR screen conducted in a CD4+ T cell leukemia line has identified host factors required for HIV infection but dispensable for cellular survival. The results highlight sulfation on the HIV co-receptor CCR5 and cellular aggregation as potential targets for therapeutic intervention.
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24
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Stewart-Hutchinson PJ, Szasz TP, Jaeger ER, Onken MD, Cooper JA, Morley SC. Technical Advance: New in vitro method for assaying the migration of primary B cells using an endothelial monolayer as substrate. J Leukoc Biol 2017. [PMID: 28637896 DOI: 10.1189/jlb.1ta0117-008r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Migration of B cells supports their development and recruitment into functional niches. Therefore, defining factors that control B cell migration will lead to a better understanding of adaptive immunity. In vitro cell migration assays with B cells have been limited by poor adhesion of cells to glass coated with adhesion molecules. We have developed a technique using monolayers of endothelial cells as the substrate for B cell migration and used this technique to establish a robust in vitro assay for B cell migration. We use TNF-α to up-regulate surface expression of the adhesion molecule VCAM-1 on endothelial cells. The ligand VLA-4 is expressed on B cells, allowing them to interact with the endothelial monolayer and migrate on its surface. We tested our new method by examining the role of L-plastin (LPL), an F-actin-bundling protein, in B cell migration. LPL-deficient (LPL-/-) B cells displayed decreased speed and increased arrest coefficient compared with wild-type (WT) B cells, following chemokine stimulation. However, the confinement ratios for WT and LPL-/- B cells were similar. Thus, we demonstrate how the use of endothelial monolayers as a substrate will support future interrogation of molecular pathways essential to B cell migration.
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Affiliation(s)
- Phillip J Stewart-Hutchinson
- Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Taylor P Szasz
- Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Emily R Jaeger
- Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Michael D Onken
- Departments of Biochemistry and Molecular Biophysics and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA; and
| | - John A Cooper
- Departments of Biochemistry and Molecular Biophysics and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA; and
| | - Sharon Celeste Morley
- Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA; .,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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25
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Park RJ, Wang T, Koundakjian D, Hultquist JF, Lamothe-Molina P, Monel B, Schumann K, Yu H, Krupzcak KM, Garcia-Beltran W, Piechocka-Trocha A, Krogan NJ, Marson A, Sabatini DM, Lander ES, Hacohen N, Walker BD. A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors. Nat Genet 2016; 49:193-203. [PMID: 27992415 DOI: 10.1038/ng.3741] [Citation(s) in RCA: 244] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/15/2016] [Indexed: 12/14/2022]
Abstract
Host proteins are essential for HIV entry and replication and can be important nonviral therapeutic targets. Large-scale RNA interference (RNAi)-based screens have identified nearly a thousand candidate host factors, but there is little agreement among studies and few factors have been validated. Here we demonstrate that a genome-wide CRISPR-based screen identifies host factors in a physiologically relevant cell system. We identify five factors, including the HIV co-receptors CD4 and CCR5, that are required for HIV infection yet are dispensable for cellular proliferation and viability. Tyrosylprotein sulfotransferase 2 (TPST2) and solute carrier family 35 member B2 (SLC35B2) function in a common pathway to sulfate CCR5 on extracellular tyrosine residues, facilitating CCR5 recognition by the HIV envelope. Activated leukocyte cell adhesion molecule (ALCAM) mediates cell aggregation, which is required for cell-to-cell HIV transmission. We validated these pathways in primary human CD4+ T cells through Cas9-mediated knockout and antibody blockade. Our findings indicate that HIV infection and replication rely on a limited set of host-dispensable genes and suggest that these pathways can be studied for therapeutic intervention.
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Affiliation(s)
- Ryan J Park
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA.,Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA
| | - Tim Wang
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.,David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA
| | - Dylan Koundakjian
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA
| | - Judd F Hultquist
- Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biosciences, QB3, University of California at San Francisco (UCSF), San Francisco, California, USA.,Gladstone Institute of Virology and Immunology, J. David Gladstone Institutes, San Francisco, California, USA
| | - Pedro Lamothe-Molina
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA.,Biological Sciences in Public Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Blandine Monel
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA.,Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kathrin Schumann
- Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA
| | - Haiyan Yu
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA
| | - Kevin M Krupzcak
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Wilfredo Garcia-Beltran
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA.,Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA
| | - Alicja Piechocka-Trocha
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA
| | - Nevan J Krogan
- Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biosciences, QB3, University of California at San Francisco (UCSF), San Francisco, California, USA.,Gladstone Institute of Virology and Immunology, J. David Gladstone Institutes, San Francisco, California, USA
| | - Alexander Marson
- Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California, USA.,Diabetes Center, University of California at San Francisco, San Francisco, California, USA.,Department of Medicine, University of California at San Francisco, San Francisco, California, USA.,Innovative Genomics Initiative (IGI), University of California, Berkeley, Berkeley, California, USA.,UCSF Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA
| | - David M Sabatini
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.,David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.,Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Eric S Lander
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Nir Hacohen
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.,Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Bruce D Walker
- Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Cambridge, Massachusetts, USA.,Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.,Howard Hughes Medical Institute, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Institute of Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Capece T, Kim M. The Role of Lymphatic Niches in T Cell Differentiation. Mol Cells 2016; 39:515-23. [PMID: 27306645 PMCID: PMC4959015 DOI: 10.14348/molcells.2016.0089] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 05/21/2016] [Accepted: 05/24/2016] [Indexed: 11/27/2022] Open
Abstract
Long-term immunity to many viral and bacterial pathogens requires CD8(+) memory T cell development, and the induction of long-lasting CD8(+) memory T cells from a naïve, undifferentiated state is a major goal of vaccine design. Formation of the memory CD8(+) T cell compartment is highly dependent on the early activation cues received by naïve CD8(+) T cells during primary infection. This review aims to highlight the cellularity of various niches within the lymph node and emphasize recent evidence suggesting that distinct types of T cell activation and differentiation occur within different immune contexts in lymphoid organs.
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Affiliation(s)
- Tara Capece
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642,
USA
| | - Minsoo Kim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642,
USA
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Liu JR, Han X, Soriano SG, Yuki K. Leukocyte function-associated antigen-1 deficiency impairs responses to polymicrobial sepsis. World J Clin Cases 2015; 3:793-806. [PMID: 26380827 PMCID: PMC4568529 DOI: 10.12998/wjcc.v3.i9.793] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 04/10/2015] [Accepted: 06/15/2015] [Indexed: 02/05/2023] Open
Abstract
AIM To determine the role of leukocyte function-associated antigen-1 (LFA-1) in polymicrobial sepsis model in mice. METHODS Cecal ligation and puncture model was used to study polymicrobial sepsis in wild type and LFA-1 knockout (KO) (= CD11a KO) mice. Their survivals were examined. Neutrophil recruitment to the abdominal cavity, bacterial tissue load and bacterial killing by neutrophils, tissue cytokine profiles, and serum cytokines were examined. Apoptosis of tissues was assessed using cleaved-caspase 3 and TUNNEL staining. The recruitment of neutrophils to various tissues was assessed using myeloperoxidase staining or measuring myeloperoxidase activity. RESULTS LFA-1 deficiency significantly decreased survival (P = 0.0024) with the reduction of neutrophil recruitment to the abdominal cavity and higher bacterial load in blood. It was also associated with increased apoptosis in spleen and more organ injuries probed by interleukin-6 mRNA level. However, the deficiency of LFA-1 did not prevent neutrophil recruitment to lung, liver, spleen or kidney, which suggested the existence of LFA-1 independent recruitment mechanism in these organs. CONCLUSION LFA-1 deficiency did not attenuate neutrophil recruitment to various organs to adequately mitigate secondary tissue injury in sepsis. It was associated with decreased neutrophil recruitment to the abdominal cavity, higher bacterial load, leading to increased mortality in an abdominal, polymicrobial sepsis.
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28
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Ivanyi J. Local Immune Responses in Tuberculosis. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00095-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus. Semin Immunol 2014; 26:559-77. [PMID: 25311810 DOI: 10.1016/j.smim.2014.09.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 09/17/2014] [Accepted: 09/19/2014] [Indexed: 12/31/2022]
Abstract
Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease--the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage.
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Roberts LL, Robinson CM. Mycobacterium tuberculosis infection of human dendritic cells decreases integrin expression, adhesion and migration to chemokines. Immunology 2014; 141:39-51. [PMID: 23981064 DOI: 10.1111/imm.12164] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 08/19/2013] [Accepted: 08/20/2013] [Indexed: 12/25/2022] Open
Abstract
Tuberculosis (TB) remains a major global health problem accounting for millions of deaths annually. Approximately one-third of the world's population is infected with the causative agent Mycobacterium tuberculosis. The onset of an adaptive immune response to M. tuberculosis is delayed compared with other microbial infections. This delay permits bacterial growth and dissemination. The precise mechanism(s) responsible for this delay have remained obscure. T-cell activation is preceded by dendritic cell (DC) migration from infected lungs to local lymph nodes and synapsis with T cells. We hypothesized that M. tuberculosis may impede the ability of DCs to reach lymph nodes and initiate an adaptive immune response. We used primary human DCs to determine the effect of M. tuberculosis on expression of heterodimeric integrins involved in cellular adhesion and migration. We also evaluated the ability of infected DCs to adhere to and migrate through lung endothelial cells, which is necessary to reach lymph nodes. We show by flow cytometry and confocal microscopy that M. tuberculosis-infected DCs exhibit a significant reduction in surface expression of the β(2) (CD18) integrin. Distribution of integrin β(2) is also markedly altered in M. tuberculosis-infected DCs. A corresponding reduction in the αL (CD11a) and αM (CD11b) subunits that associate with integrin β(2) was also observed. Consistent with reduced integrin surface expression, we show a significant reduction in adherence to lung endothelial cell monolayers and migration towards lymphatic chemokines when DCs are infected with M. tuberculosis. These findings suggest that M. tuberculosis modulates DC adhesion and migration to increase the time required to initiate an adaptive immune response.
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Affiliation(s)
- Lawton L Roberts
- Department of Pathology, Microbiology, & Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
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31
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Yuan ML, Tong ZH, Jin XG, Zhang JC, Wang XJ, Ma WL, Yin W, Zhou Q, Ye H, Shi HZ. Regulation of CD4(+) T cells by pleural mesothelial cells via adhesion molecule-dependent mechanisms in tuberculous pleurisy. PLoS One 2013; 8:e74624. [PMID: 24069325 PMCID: PMC3777994 DOI: 10.1371/journal.pone.0074624] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 08/04/2013] [Indexed: 11/25/2022] Open
Abstract
Background Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been demonstrated to be expressed on pleural mesothelial cells (PMCs), and to mediate leukocyte adhesion and migration; however, little is known about whether adhesion molecule-dependent mechanisms are involved in the regulation of CD4+ T cells by PMCs in tuberculous pleural effusion (TPE). Methods Expressions of ICAM-1 and VCAM-1 on PMCs, as well as expressions of CD11a and CD29, the counter-receptors for ICAM-1 and VCAM-1, respectively, expressed on CD4+ T cells in TPE were determined using flow cytometry. The immune regulations on adhesion, proliferation, activation, selective expansion of CD4+ helper T cell subgroups exerted by PMCs via adhesion molecule-dependent mechanisms were explored. Results Percentages of ICAM-1-positive and VCAM-1‒positive PMCs in TPE were increased compared with PMC line. Interferon-γ enhanced fluorescence intensity of ICAM-1, while IL-4 promoted VCAM-1 expression on PMCs. Percentages of CD11ahighCD4+ and CD29highCD4+ T cells in TPE significantly increased as compared with peripheral blood. Prestimulation of PMCs with anti‒ICAM-1 or ‒VCAM-1 mAb significantly inhibited adhesion, activation, as well as effector regulatory T cell expansion induced by PMCs. Conclusions Our current data showed that adhesion molecule pathways on PMCs regulated adhesion and activation of CD4+ T cells, and selectively promoted the expansion of effector regulatory T cells.
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Affiliation(s)
- Ming-Li Yuan
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhao-Hui Tong
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Center of Medical Research, Beijing Institute of Respiratory Diseases, Beijing, China
| | - Xiao-Guang Jin
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jian-Chu Zhang
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Juan Wang
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Wan-Li Ma
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Yin
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiong Zhou
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Ye
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan-Zhong Shi
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center of Medical Research, Beijing Institute of Respiratory Diseases, Beijing, China
- * E-mail:
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CD11a regulates effector CD8 T cell differentiation and central memory development in response to infection with Listeria monocytogenes. Infect Immun 2013; 81:1140-51. [PMID: 23357382 DOI: 10.1128/iai.00749-12] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
β2 (CD18) integrins with α-chains CD11a, -b, -c, and -d are important adhesion molecules necessary for leukocyte migration and cellular interactions. CD18 deficiency leads to recurrent bacterial infections and poor wound healing due to reduced migration of leukocytes to inflammatory sites. CD8 T cells also upregulate CD11a, CD11b, and CD11c upon activation. However, the role these molecules play for CD8 T cells in vivo is not known. To determine the function of individual β2 integrins, we examined CD8 T cell responses to Listeria monocytogenes infection in CD11a-, CD11b-, and CD11c-deficient mice. The absence of CD11b or CD11c had no effect on the generation of antigen-specific CD8 T cells. In contrast, the magnitude of the primary CD8 T cell response in CD11a-deficient mice was significantly reduced. Moreover, the response in CD11a(-/-) mice exhibited reduced differentiation of short-lived effector cells (KLRG1(hi) CD127(lo)), although cytokine and granzyme B production levels were unaffected. Notably, CD11a deficiency resulted in greatly enhanced generation of CD62L(+) central memory cells. Surprisingly, CD8 T cells lacking CD11a mounted a robust secondary response to infection. Taken together, these findings demonstrated that CD11a expression contributes to expansion and differentiation of primary CD8 T cells but may be dispensable for secondary responses to infection.
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Druszczynska M, Wlodarczyk M, Janiszewska-Drobinska B, Kielnierowski G, Zawadzka J, Kowalewicz-Kulbat M, Fol M, Szpakowski P, Rudnicka K, Chmiela M, Rudnicka W. Monocyte signal transduction receptors in active and latent tuberculosis. Clin Dev Immunol 2013; 2013:851452. [PMID: 23401703 PMCID: PMC3562648 DOI: 10.1155/2013/851452] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Revised: 12/18/2012] [Accepted: 12/18/2012] [Indexed: 11/17/2022]
Abstract
The mechanisms that promote either resistance or susceptibility to TB disease remain insufficiently understood. Our aim was to compare the expression of cell signaling transduction receptors, CD14, TLR2, CD206, and β2 integrin LFA-1 on monocytes from patients with active TB or nonmycobacterial lung disease and healthy individuals with M.tb latency and uninfected controls to explain the background of the differences between clinical and subclinical forms of M.tb infection. A simultaneous increase in the expression of the membrane bound mCD14 receptor and LFA-1 integrin in patients with active TB may be considered a prodrome of breaking immune control by M.tb bacilli in subjects with the latent TB and absence of clinical symptoms.
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Affiliation(s)
- Magdalena Druszczynska
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Marcin Wlodarczyk
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Beata Janiszewska-Drobinska
- Regional Specialized Hospital of Tuberculosis, Lung Diseases and Rehabilitation, Szpitalna 5, 95-080 Tuszyn, Poland
| | - Grzegorz Kielnierowski
- Regional Specialized Hospital of Tuberculosis, Lung Diseases and Rehabilitation, Szpitalna 5, 95-080 Tuszyn, Poland
| | - Joanna Zawadzka
- Regional Specialized Hospital of Tuberculosis, Lung Diseases and Rehabilitation, Szpitalna 5, 95-080 Tuszyn, Poland
| | - Magdalena Kowalewicz-Kulbat
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Marek Fol
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Piotr Szpakowski
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Karolina Rudnicka
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Magdalena Chmiela
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Wieslawa Rudnicka
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
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Salem S, Gros P. Genetic Determinants of Susceptibility to Mycobacterial Infections: IRF8, A New Kid on the Block. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 783:45-80. [DOI: 10.1007/978-1-4614-6111-1_3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Understanding delayed T-cell priming, lung recruitment, and airway luminal T-cell responses in host defense against pulmonary tuberculosis. Clin Dev Immunol 2012; 2012:628293. [PMID: 22545059 PMCID: PMC3321538 DOI: 10.1155/2012/628293] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 01/18/2012] [Indexed: 11/18/2022]
Abstract
Mycobacterium tuberculosis (M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central to M.tb effective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intracellular bacterial lung pathogens, such as Legionella pneumophila, or even closely related mycobacterial species such as M. smegmatis, this delay is astonishing. Customarily, the alveolar macrophage (AM) acts as a sentinel, detecting and alerting surrounding cells to the presence of an invader. However, in the case of M.tb, this may be impaired, thus delaying the recruitment of antigen-presenting cells (APCs) to the lung. Upon uptake by APC populations, M.tb is able to subvert and delay the processing of antigen, MHC class II loading, and the priming of effector T cell populations. This delay ultimately results in the deferred recruitment of effector T cells to not only the lung interstitium but also the airway lumen. Therefore, it is of upmost importance to dissect the mechanisms that contribute to the delayed onset of immune responses following M.tb infection. Such knowledge will help design the most effective vaccination strategies against pulmonary TB.
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Interplay of polarity proteins and GTPases in T-lymphocyte function. Clin Dev Immunol 2012; 2012:417485. [PMID: 22461835 PMCID: PMC3296228 DOI: 10.1155/2012/417485] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 12/13/2011] [Indexed: 01/16/2023]
Abstract
Polarity refers to the asymmetric distribution of different cellular components within a cell and is central to many cell functions. In T-cells, polarity regulates the activation, migration, and effector function of cytotoxic T-cells (CTLs) during an immune response. The regulation of asymmetric cell division by polarity proteins may also dictate CTL effector and memory differentiation following antigen presentation. Small GTPases, along with their associated polarity and adaptor proteins, are critical for mediating the polarity changes necessary for T-cell activation and function, and in turn, are regulated by guanine exchange factors (GEFS) and GTPase activating proteins (GAPS). For example, a novel GEF, dedicator of cytokinesis 8 (DOCK8) was recently identified as a regulator of immune cell function and mutations in DOCK8 have been detected in patients with severe combined immunodeficiency. Both B and T-cells from DOCK8 mutant mice form defective immunological synapses and have abnormal functions, in addition to impaired immune memory development. This paper will discuss the interplay between polarity proteins and GTPases, and their role in T-cell function.
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Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM) cells which expand following virulent mycobacterial challenge. PLoS One 2011; 6:e21566. [PMID: 21720558 PMCID: PMC3123368 DOI: 10.1371/journal.pone.0021566] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 06/02/2011] [Indexed: 12/22/2022] Open
Abstract
To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (TEM) cells in vaccinated mice. These CD4+CD44hiCD62LloCD27− T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or ‘quality of response’ than single cytokine producing cells. These cells are maintained for long periods (>16 months) in BCG protected mice, maintaining a vaccine–specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of TEM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional TEM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific TEM in the lung may represent a new generation of TB vaccines.
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Kadioglu A, De Filippo K, Bangert M, Fernandes VE, Richards L, Jones K, Andrew PW, Hogg N. The integrins Mac-1 and alpha4beta1 perform crucial roles in neutrophil and T cell recruitment to lungs during Streptococcus pneumoniae infection. THE JOURNAL OF IMMUNOLOGY 2011; 186:5907-15. [PMID: 21460207 DOI: 10.4049/jimmunol.1001533] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Neutrophils and T cells play an important role in host protection against pulmonary infection caused by Streptococcus pneumoniae. However, the role of the integrins in recruitment of these cells to infected lungs is not well understood. In this study we used the twin approaches of mAb blockade and gene-deficient mice to investigate the relative impact of specific integrins on cellular recruitment and bacterial loads following pneumococcal infection. We find that both Mac-1 (CD11b/CD18) and α(4)β(1) (CD49d/CD29) integrins, but surprisingly not LFA-1 (CD11a/CD18), contribute to two aspects of the response. In terms of recruitment from the circulation into lungs, neutrophils depend on Mac-1 and α(4)β(1), whereas the T cells are entirely dependent on α(4)β(1). Second, immunohistochemistry results indicate that adhesion also plays a role within infected lung tissue itself. There is widespread expression of ICAM-1 within lung tissue. Use of ICAM-1(-/-) mice revealed that neutrophils make use of this Mac-1 ligand, not for lung entry or for migration within lung tissue, but for combating the pneumococcal infection. In contrast to ICAM-1, there is restricted and constitutive expression of the α(4)β(1) ligand, VCAM-1, on the bronchioles, allowing direct access of the leukocytes to the airways via this integrin at an early stage of pneumococcal infection. Therefore, integrins Mac-1 and α(4)β(1) have a pivotal role in prevention of pneumococcal outgrowth during disease both in regulating neutrophil and T cell recruitment into infected lungs and by influencing their behavior within the lung tissue itself.
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Affiliation(s)
- Aras Kadioglu
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, United Kingdom.
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Kang DD, Lin Y, Moreno JR, Randall TD, Khader SA. Profiling early lung immune responses in the mouse model of tuberculosis. PLoS One 2011; 6:e16161. [PMID: 21249199 PMCID: PMC3020951 DOI: 10.1371/journal.pone.0016161] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 12/08/2010] [Indexed: 01/01/2023] Open
Abstract
Tuberculosis (TB) is caused by the intracellular bacteria Mycobacterium tuberculosis, and kills more than 1.5 million people every year worldwide. Immunity to TB is associated with the accumulation of IFNγ-producing T helper cell type 1 (Th1) in the lungs, activation of M.tuberculosis-infected macrophages and control of bacterial growth. However, very little is known regarding the early immune responses that mediate accumulation of activated Th1 cells in the M.tuberculosis-infected lungs. To define the induction of early immune mediators in the M.tuberculosis-infected lung, we performed mRNA profiling studies and characterized immune cells in M.tuberculosis-infected lungs at early stages of infection in the mouse model. Our data show that induction of mRNAs involved in the recognition of pathogens, expression of inflammatory cytokines, activation of APCs and generation of Th1 responses occurs between day 15 and day 21 post infection. The induction of these mRNAs coincides with cellular accumulation of Th1 cells and activation of myeloid cells in M.tuberculosis-infected lungs. Strikingly, we show the induction of mRNAs associated with Gr1+ cells, namely neutrophils and inflammatory monocytes, takes place on day 12 and coincides with cellular accumulation of Gr1+ cells in M.tuberculosis-infected lungs. Interestingly, in vivo depletion of Gr1+ neutrophils between days 10-15 results in decreased accumulation of Th1 cells on day 21 in M.tuberculosis-infected lungs without impacting overall protective outcomes. These data suggest that the recruitment of Gr1+ neutrophils is an early event that leads to production of chemokines that regulate the accumulation of Th1 cells in the M.tuberculosis-infected lungs.
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Affiliation(s)
- Dongwan D. Kang
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Yinyao Lin
- Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Javier-Rangel Moreno
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Troy D. Randall
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Shabaana A. Khader
- Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
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Okamoto Yoshida Y, Umemura M, Yahagi A, O'Brien RL, Ikuta K, Kishihara K, Hara H, Nakae S, Iwakura Y, Matsuzaki G. Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. THE JOURNAL OF IMMUNOLOGY 2010; 184:4414-22. [PMID: 20212094 DOI: 10.4049/jimmunol.0903332] [Citation(s) in RCA: 316] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A-dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR gammadelta T cells expressing TCR Vgamma4 or Vgamma6 were identified as the major IL-17A-producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A-producing TCR gammadelta T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A-producing TCR gammadelta T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR gammadelta T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.
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Affiliation(s)
- Yuko Okamoto Yoshida
- Tropical Biosphere Research Center, Division of Host Defense and Vaccinology, Department of Microbiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
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Abstract
Although critical for cell adhesion and migration during normal immune-mediated reactions, leukocyte integrins are also involved in the pathogenesis of diverse clinical conditions including autoimmune diseases and chronic inflammation. Leukocyte integrins therefore have been targets for anti-adhesive therapies to treat the inflammatory disorders. Recently, the therapeutic potential of integrin antagonists has been demonstrated in psoriasis and multiple sclerosis. However, current therapeutics broadly affect integrin functions and, thus, yield unfavorable side effects. This review discusses the major leukocyte integrins and the anti-adhesion strategies for treating immune diseases.
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Affiliation(s)
- Young-Min Hyun
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, NY 14642, USA
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Mizukawa Y, Shiohara T. Fixed drug eruption: a prototypic disorder mediated by effector memory T cells. Curr Allergy Asthma Rep 2009; 9:71-7. [PMID: 19063828 DOI: 10.1007/s11882-009-0011-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Effector memory T cells are uniquely specialized to mediate protective immunity. However, their excessive activation may result in the development of organ-specific inflammatory diseases, which have not been extensively studied. Fixed drug eruption (FDE), a localized variant of drug-induced dermatoses characterized by relapse in the same location, is a prototypic disorder mediated by excessive activation of effector memory T cells, which are resident in the lesional epidermis. A variety of clinical and pathologic features uniquely observed in FDE lesions can be explained by the presence of CD8(+) intraepidermal T cells with the effector memory phenotype in the FDE lesion. This review focuses on how these T cells are generated, retained in the epidermis, and activated to cause epidermal damage.
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Affiliation(s)
- Yoshiko Mizukawa
- Department of Dermatology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
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Hoang TTKT, Nansen A, Roy S, Billeskov R, Aagaard C, Elvang T, Dietrich J, Andersen P. Distinct differences in the expansion and phenotype of TB10.4 specific CD8 and CD4 T cells after infection with Mycobacterium tuberculosis. PLoS One 2009; 4:e5928. [PMID: 19529765 PMCID: PMC2691482 DOI: 10.1371/journal.pone.0005928] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Accepted: 04/27/2009] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Recently we and others have identified CD8 and CD4 T cell epitopes within the highly expressed M. tuberculosis protein TB10.4. This has enabled, for the first time, a comparative study of the dynamics and function of CD4 and CD8 T cells specific for epitopes within the same protein in various stages of TB infection. METHODS AND FINDINGS We focused on T cells directed to two epitopes in TB10.4; the MHC class I restricted epitope TB10.4 (3-11) (CD8/10.4 T cells) and the MHC class II restricted epitope TB10.4 (74-88) (CD4/10.4 T cells). CD4/10.4 and CD8/10.4 T cells displayed marked differences in terms of expansion and contraction in a mouse TB model. CD4/10.4 T cells dominated in the early phase of infection whereas CD8/10.4 T cells were expanded after week 16 and reached 5-8 fold higher numbers in the late phase of infection. In the early phase of infection both CD4/10.4 and CD8/10.4 T cells were characterized by 20-25% polyfunctional cells (IL-2(+), IFN-gamma(+), TNF-alpha(+)), but whereas the majority of CD4/10.4 T cells were maintained as polyfunctional T cells throughout infection, CD8/10.4 T cells differentiated almost exclusively into effector cells (IFN-gamma(+), TNF-alpha(+)). Both CD4/10.4 and CD8/10.4 T cells exhibited cytotoxicity in vivo in the early phase of infection, but whereas CD4/10.4 cell mediated cytotoxicity waned during the infection, CD8/10.4 T cells exhibited increasing cytotoxic potential throughout the infection. CONCLUSIONS/SIGNIFICANCE Our results show that CD4 and CD8 T cells directed to epitopes in the same antigen differ both in their kinetics and functional characteristics throughout an infection with M. tuberculosis. In addition, the observed strong expansion of CD8 T cells in the late stages of infection could have implications for the development of post exposure vaccines against latent TB.
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Affiliation(s)
| | - Anneline Nansen
- Department of Immunopharmacology, Novo Nordisk, Måløv, Denmark
| | - Sugata Roy
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
| | - Rolf Billeskov
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
| | - Claus Aagaard
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
| | - Tara Elvang
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
| | - Jes Dietrich
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
- * E-mail: (JD); (PA)
| | - Peter Andersen
- Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark
- * E-mail: (JD); (PA)
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Windish HP, Lin PL, Mattila JT, Green AM, Onuoha EO, Kane LP, Flynn JL. Aberrant TGF-beta signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis. J Leukoc Biol 2009; 86:713-25. [PMID: 19454651 DOI: 10.1189/jlb.1208740] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Foxp3+ T regulatory cells are required to prevent autoimmune disease, but also prevent clearance of some chronic infections. While natural T regulatory cells are produced in the thymus, TGF-beta1 signaling combined with T-cell receptor signaling induces the expression of Foxp3 in CD4+ T cells in the periphery. We found that ICAM-1-/- mice have fewer T regulatory cells in the periphery than WT controls, due to a role for ICAM-1 in induction of Foxp3 expression in response to TGF-beta1. Further investigation revealed a functional deficiency in the TGF-beta1-induced translocation of phosphorylated Smad3 from the cytoplasmic compartment to the nucleus in ICAM-1-deficient mice. This impairment in the TGF-beta1 signaling pathway is most likely responsible for the decrease in T regulatory cell induction in the absence of ICAM-1. We hypothesized that in the presence of an inflammatory response, reduced production of inducible T regulatory cells would be evident in ICAM-1-/- mice. Indeed, following Mycobacterium tuberculosis infection, ICAM-1-/- mice had a pronounced reduction in T regulatory cells in the lungs compared with control mice. Consequently, the effector T-cell response and inflammation were greater in the lungs of ICAM-1-/- mice, resulting in morbidity due to overwhelming pathology.
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Affiliation(s)
- Hillarie Plessner Windish
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Taylor JL, Bielefeldt-Ohmann H, Pozzi A, Izzo AA. Lack of alpha-1 integrin alters lesion morphology during pulmonary Mycobacterium tuberculosis infection. Tuberculosis (Edinb) 2008; 88:444-52. [PMID: 18639492 PMCID: PMC2613756 DOI: 10.1016/j.tube.2008.05.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Revised: 05/01/2008] [Accepted: 05/19/2008] [Indexed: 11/16/2022]
Abstract
The hallmark of Mycobacterium tuberculosis infection is the granuloma, a highly dynamic immune structure that contains the bacilli during chronic infection. Here, we examined if alpha1beta1 integrin is required in the development and maintenance of the granulomatous structure during pulmonary infection using the alpha1 integrin knockout (alpha1-null) mouse. The alpha1beta1 integrin is expressed on activated macrophages and T cells, and interacts with collagen molecules in the extracellular matrix (ECM), and thus may play a role in the granulomatous process. Following pulmonary infection with virulent M. tuberculosis, lungs of alpha1-null infected mice had striking differences in granuloma structure, as well as distinct and markedly thickened alveolar septae. By day 180, there were regions of cell death within granulomatous lesions, characterized by cellular debris in these mice. To determine if this molecule was necessary for T cell trafficking within the lungs, the expression of CD4, CD44 and CD62L was monitored. The number of activated and IFN-gamma-producing CD4+ T cells increased in the lungs of alpha1-null mice during the chronic phase of infection, although they had decreased concentrations of TNF-alpha and MMP-9. These results suggest that while alpha1beta1 integrin is not required for trafficking or maintenance of T cells in M. tuberculosis infected lungs, it does play a role in granuloma structure and integrity during the chronic phase of infection.
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Affiliation(s)
- Jennifer L Taylor
- Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
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Miyazaki Y, Bunting M, Stafforini DM, Harris ES, McIntyre TM, Prescott SM, Frutuoso VS, Amendoeira FC, de Oliveira Nascimento D, Vieira-de-Abreu A, Weyrich AS, Castro-Faria-Neto HC, Zimmerman GA. Integrin alphaDbeta2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 180:590-600. [PMID: 18097061 PMCID: PMC2275910 DOI: 10.4049/jimmunol.180.1.590] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin alphaDbeta2, a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. alphaDbeta2 is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity. In response to challenge with Plasmodium berghei, a malarial pathogen that models systemic infection and inflammatory injury, new populations of alphaD+ macrophages evolved in the spleen and liver. Unexpectedly, targeted deletion of alphaD conferred a survival advantage in P. berghei infection over a 30-day observation period. Mechanistic studies demonstrated that the increased survival of alphaD-/- animals at these time points is not attributed to differences in magnitude of anemia or parasitemia or to alterations in splenic microanatomy, each of which is a key variable in the natural history of P. berghei infection, and indicated that an altered pattern of inflammatory cytokines may contribute to the difference in mortality. In contrast to the outcome in malarial challenge, death of alphaD-/- animals was accelerated in a model of Salmonella sepsis, demonstrating differential rather than stereotyped roles for alphaDbeta2 in systemic infection. These studies identify previously unrecognized and unique activities of alphaDbeta2, and macrophages that express it, in host defense and injury.
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Affiliation(s)
- Yasunari Miyazaki
- Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
| | - Michaeline Bunting
- Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
| | - Diana M. Stafforini
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
| | - Estelle S. Harris
- Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
| | - Thomas M. McIntyre
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
- Department of Pathology, University of Utah, Salt Lake City, UT 84112
| | - Stephen M. Prescott
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
| | - Valber S. Frutuoso
- Laboratório de Immunofarmacologia, Departmento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Fabio C. Amendoeira
- Laboratório de Immunofarmacologia, Departmento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Danielle de Oliveira Nascimento
- Laboratório de Immunofarmacologia, Departmento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Adriana Vieira-de-Abreu
- Laboratório de Immunofarmacologia, Departmento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Andrew S. Weyrich
- Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
| | - Hugo C. Castro-Faria-Neto
- Laboratório de Immunofarmacologia, Departmento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Guy A. Zimmerman
- Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112
- Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112
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Castriconi R, Dondero A, Cantoni C, Della Chiesa M, Prato C, Nanni M, Fiorini M, Notarangelo L, Parolini S, Moretta L, Notarangelo L, Moretta A, Bottino C. Functional characterization of natural killer cells in type I leukocyte adhesion deficiency. Blood 2007; 109:4873-81. [PMID: 17272509 DOI: 10.1182/blood-2006-08-038760] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Abstract
In this study, we analyzed IL-2–activated polyclonal natural killer (NK) cells derived from 2 patients affected by leukocyte adhesion deficiency type I (LAD1), an immunodeficiency characterized by mutations of the gene coding for CD18, the β subunit shared by major leukocyte integrins. We show that LAD1 NK cells express normal levels of various triggering NK receptors (and coreceptors) and that mAb-mediated engagement of these receptors results in the enhancement of both NK cytolytic activity and cytokine production. Moreover, these activating NK receptors were capable of recognizing their specific ligands on target cells. Thus, LAD1 NK cells, similarly to normal NK cells, were capable of killing most human tumor cells analyzed and produced high amounts of IFN-γ when cocultured in presence of target cells. Murine target cells represented a common exception, as they were poorly susceptible to LAD1 NK cells. Finally, LAD1 NK cells could efficiently kill or induce maturation of monocyte-derived immature dendritic cells (DCs). Altogether our present study indicates that in LAD1 patients, 3 important functions of NK cells (eg, cytotoxicity, IFN-γ production, and DC editing) are only marginally affected and provides new insight on the cooperation between activating receptors and LFA-1 in the induction of NK cell activation and function.
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Affiliation(s)
- Roberta Castriconi
- Dipartimento di Medicina Sperimentale, Istituto Giannina Gaslini, University of Genoa, Largo G. Gaslini 5, 16147 Genoa, Italy
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