Identical β Cell-Specific CD8+ T Cell Clonotypes Typically Reside in Both Peripheral Blood Lymphocyte and Pancreatic Islets

Wong, Carmen P.; Stevens, R. H.; Long, Brian; Li, Li; Wang, Yaming; Wallet, Mark A.; Goudy, Kevin; Frelinger, Jeffrey A.; Tisch, Roland

doi:10.4049/jimmunol.178.3.1388

Cited by 34 publications

(38 citation statements)

References 35 publications

(49 reference statements)

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“…We also observed a lower frequency of these cells in PLNs and peripheral blood of Socs1-tg mice. This is in agreement with previous studies showing that the frequency of IGRP206-214-specific CD8+ T cells in the blood reflects the frequency in the pancreas and can predict disease development in NOD mice [6,19].…”

Section: Discussionsupporting

confidence: 82%

“…Lower frequency of self-reactive T cells in pancreas, pancreatic lymph nodes (PLNs) and peripheral blood of Socs1-tg NOD mice The risk of diabetes development correlates with the frequency of islet-specific T cells in the peripheral blood and pancreas of NOD mice [6,19]. Isletspecific glucose 6-phosphatase catalytic subunit-related protein (IGRP) 206-214-specific CD8+ T cells, identified using H-2K d tetramers complexed with the high-affinity NRPV7 mimetic peptide, become particularly prominent during the weeks just before diabetes onset [6,20,21].…”

Section: Resultsmentioning

confidence: 99%

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The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice

et al. 2008

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Aims/hypothesis The pancreatic beta cell response to cytokines is crucial for the development of type 1 diabetes in the NOD mouse. For example, beta cell production of suppressor of cytokine signalling-1 (SOCS-1) protects against diabetes. This finding and other recent studies indicated that cytokine-stressed beta cells might contribute to disease progression by affecting the pancreatic lymphocyte infiltrate. The aim of this study was to provide insight into how the beta cell influences the pancreas-infiltrating T cell repertoire. Methods Lymphocytes isolated from Socs1-transgenic (tg) and non-tg NOD mice were analysed by flow cytometry. mRNA and protein levels in pancreatic islets were measured by real-time PCR and immunofluorescence analysis, respectively.Results The percentages of regulatory T cells, total counts and ratios between infiltrating CD8+ and CD4+ T cells, and the expression of killer cell lectin-like receptor subfamily K, member 1 (NKG2D) on CD8+ T cells did not differ in pancreases from prediabetic Socs1-tg and non-tg NOD mice. However, a striking difference in the percentages of CD8+ T cells specific for glucose 6-phosphatase catalytic subunit-related protein 206-214 was found, showing that SOCS-1 prevents the accumulation of high percentages of self-reactive CD8+ T cells in the pancreas. It was also found that protection from diabetes in Socs1-tg NOD mice correlated with a reduced expression of Cxcl10 mRNA in IFN-γ treated islets. Conclusions/interpretation This study highlights an important role for the beta cell in the local regulation of the diabetogenic process. By responding to the pro-inflammatory pancreas milieu it strongly influences the islet-reactive T cell repertoire in the pancreas.Keywords Diabetes . Interferon . Non-obese diabetic mouse . Pancreas . Suppressor of cytokine signalling-1 Abbreviations CFSE 5-(and 6-) carboxyfluorescein diacetate succinimidyl ester CXCL10 chemokine (C-X-C motif) ligand 10 CXCR3 chemokine (C-X-C motif) receptor 3 FOXP3 forkhead box P3 IGRP islet-specific glucose 6-phosphatase catalytic subunit-related protein NKG2D killer cell lectin-like receptor subfamily K, member 1 PLN pancreatic lymph node RT real time SOCS-1 suppressor of cytokine signalling-1 Diabetologia

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice

et al. 2008

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“…Accordingly, an important question is whether ␤ cell-specific T cells detected in PBL accurately reflect those T cells infiltrating the islets, and in turn provide a reliable readout to evaluate disease progression. Studies have demonstrated that clones of ␤ cell-specific CD8 ϩ T cells found in the islets also reside in PBL of NOD mice (16,17). For instance, analyses of CDR of TCR expressed by CD8 ϩ T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) demonstrated that identical clones reside in both PBL and the islets albeit at differing frequencies (16).…”

Section: T Ype 1 Diabetes (T1d)mentioning

confidence: 99%

β Cell-Specific CD4+ T Cell Clonotypes in Peripheral Blood and the Pancreatic Islets Are Distinct

Garland

et al. 2009

The Journal of Immunology

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Type 1 diabetes is an autoimmune disease mediated by β cell-specific CD4+ and CD8+ T cells. Tracking β cell-specific T cells is one approach to monitor the diabetogenic response in at risk or diabetic individuals. Such analyses, however, are limited to PBL because T cells infiltrating the pancreatic islets are normally inaccessible. A key issue is whether peripheral β cell-specific T cells accurately reflect those cells infiltrating the target tissue. We investigated the properties of CD4+ T cells specific for a mimetic epitope recognized by the BDC2.5 clonotypic TCR in NOD mice. Soluble IAg7-Ig (sIAg7-Ig) multimer complexes covalently linked to a mimetic BDC peptide (sIAg7-mBDC) were used to identify or isolate CD4+ T cells from PBL and the islets of NOD mice. A temporal increase in sIAg7-mBDC binding (g7-mBDC+) T cells corresponding with the progression of β cell autoimmunity was detected in both PBL and islets in NOD female mice. In contrast to T cells in PBL, however, the majority of islet g7-mBDC+ T cells exhibited a type 1 phenotype, and mediated diabetes upon transfer into NOD.scid recipients. TCR-β and CDR-β gene usage of single islet-infiltrating g7-mBDC+ CD4+ T cells from individual NOD mice showed a restricted repertoire dominated by one or two clones typically expressing TCR β-chain variable TRBV-15. In contrast, a distinct and diverse TCR repertoire was detected for PBL-derived g7-mBDC+ T cells. These results demonstrate that PBL and islet CD4+ T cells specific for a given β cell epitope can differ regarding pathogenicity and TCR repertoire.

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“…Some recent reports have tried to overwhelm this limit. Two studies in the mouse have suggested that, regardless the provenience of the T cells (periphery, islets, or lymph nodes), ß-cell antigen-specific CD8+ T-cell pool shares TCR chain usage [365] and show conserved patterns of epitope immunodominance [366]. Another study has performed micro array analysis of the cytokine pattern of PBMC from healthy subjects after the exposure to sera from new-onset T1D patients and has reported an enhanced secretion of pro-in ammatory factors as IL-1, CCl2, and CCl7 [367].…”

Section: T Cellsmentioning

confidence: 99%

Immunology of β-Cell Destruction

Torre

Lernmark

2010

Advances in Experimental Medicine and Biology

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Identical β Cell-Specific CD8+ T Cell Clonotypes Typically Reside in Both Peripheral Blood Lymphocyte and Pancreatic Islets

Cited by 34 publications

References 35 publications

The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice

The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice

β Cell-Specific CD4+ T Cell Clonotypes in Peripheral Blood and the Pancreatic Islets Are Distinct

Immunology of β-Cell Destruction

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