Thymic and Postthymic Regulation of Diabetogenic CD8 T Cell Development in TCR Transgenic Nonobese Diabetic (NOD) Mice

Kanagawa, Osami; Shimizu, Jun; Vaupel, Barbara A.

doi:10.4049/jimmunol.164.10.5466

Cited by 22 publications

(12 citation statements)

References 33 publications

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“…Similarly, we previously found that NOD mice transgenically expressing the TCR from an MHC class IϪrestricted ␤-cell autoreactive T-cell clone also continued to generate a relatively large number of CD4 T-cells that bypassed allelic exclusion, as evidenced by their coexpression of a second endogenously derived TCR (21). Indeed, it has been proposed that the ability to bypass allelic exclusion and express a second TCR is an important pathogenic mechanism by which ␤-cell autoreactive T-cells in NOD mice escape normal selection constraints (38). However, the higher levels of nontransgenic CD4 T-cells in NOD than in B6,D2 mice carrying the LCMV TCR Tg could also result from the known defective ability of H2-A g7 MHC class II molecules expressed in the former strain to induce immunologic tolerance (3).…”

Section: Discussionmentioning

confidence: 99%

Autoreactive Diabetogenic T-Cells in NOD Mice Can Efficiently Expand From a Greatly Reduced Precursor Pool

et al. 2001

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A broad repertoire of pancreatic ␤-cell autoreactive T-cells normally contributes to the development of type 1 diabetes in NOD mice. However, it has been unknown if a large reduction in the precursor pool from which autoreactive T-cells are drawn would inhibit the development of type 1 diabetes. To address this issue, we reduced the precursor frequency of autoreactive T-cells in NOD mice through allelic exclusion induced by transgenic expression of an H2-D b class I؊restricted T-cell receptor (TCR) specific for a pathologically irrelevant lymphocytic choriomeningitis virus (LCMV) peptide. TCR allelic exclusion greatly reduced the pool of T-cells from which diabetogenic effectors could be derived in these NOD.LCMV TCR Tg mice. Surprisingly, this did not impair their type 1 diabetes susceptibility. Furthermore, a diabetogenic CD8 T-cell population that is prevalent in standard NOD mice was present at essentially equivalent levels in pancreatic islets of NOD.LCMV TCR Tg mice. Other data indicated that the antigenic specificity of these CD8 T-cells is primarily the function of a shared TCR-␣ chain. Although the percentage of TCR transgenic T-cells decreased in NOD versus B6,D2 control mice, much higher total numbers of both the TCR transgenic and the nontransgenic T-cells accumulated in the NOD strain. This transgenic T-cell accumulation in the absence of the cognate peptide indicated that the NOD genetic background preferentially promotes a highly efficient antigen-independent T-cell expansion. This might allow diabetogenic T-cells in NOD mice to undergo an efficient expansion before encountering antigen, which would represent an important and previously unconsidered aspect of pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Autoreactive Diabetogenic T-Cells in NOD Mice Can Efficiently Expand From a Greatly Reduced Precursor Pool

et al. 2001

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“…Transgenic expression of MHC class II I-E or alternative alleles of I-A confers strong protection against T1D in NOD mice (reviewed in Ref. 90), suggesting a role for the NOD MHC class II haplotype in the selection and activation of autoreactive T cells (91)(92)(93). Furthermore, the NOD MHC contributes to isotype switch in the production of anti-insulin autoantibodies (94).…”

Section: Discussionmentioning

confidence: 99%

Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice

Chiu

Jevnikar

Danska

2001

The Journal of Immunology

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Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR Vβ3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most Vβ3+ immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed that a high frequency of NOD Vβ3+ T cells that escape deletion are activated in vivo and that this phenotype is linked to the Mtv-3 locus. One potential mechanism of SAg presentation to peripheral T cells is by activated B cells. Consistent with this idea, we found that NOD mice harbor a significantly higher frequency of activated B cells than nondiabetes-prone strains. These activated NOD B cells expressed cell surface molecules consistent with APC function. At the molecular level, the IgH repertoire of activated B cells in NOD mice was equivalent to resting B cells, suggesting a polyclonal response in vivo. Genetic analysis of the activated B cell phenotype showed linkage to Idd1, the NOD MHC haplotype (H-2g7). Finally, Vβ3+ thymocyte deletion and peripheral T cell activation did not require B cells, suggesting that other APC populations are sufficient to generate both Mtv-3-linked phenotypes. These data provide insight into the genetic regulation of NOD autoreactive lymphocyte activation that may contribute to failure of peripheral tolerance and the pathogenesis of type I diabetes.

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“…A previous report by Kanagawa and colleagues 47 demonstrated the need for I-A g7 -restricted CD4 ϩ T cells for diabetogenic CD8 ϩ T cells to cause diabetes. Deciphering the molecular details of macrophage-mediated islet ␤-cell death in our experimental mouse model will shed new insights into pathogenesis of T1DM and may identify new targets for modulation of autoimmune diabetes.…”

Section: Macrophages Kill ␤ Cells In T1dm 2143mentioning

confidence: 96%

In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing

Calderon

Suri

Unanue

2006

The American Journal of Pathology

114

113

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To understand better how diabetogenic CD4 ؉ T cells induce isletType 1 diabetes mellitus (T1DM) is an autoimmune disorder wherein the pancreatic islet ␤ cells are destroyed by autoreactive T cells resulting in a state of persistent hyperglycemia. The nonobese diabetic (NOD) mouse and the bio breeding (BB) rat are two attractive animal models for T1DM that follow many characteristics of the human disease including the expression of the diabetessusceptible class II major histocompatibility complex (MHC) alleles. 1-3 T1DM in both humans and rodents is characterized by distinct histopathological stages. The first stage, termed peri-insulitis, consists of an initial infiltration of leukocytes surrounding the islets without apparent effect on ␤ cells; this is followed by an aggressive phase wherein the infiltrate actively invades the islets and kills the ␤ cells, leading to diabetes. CD4 ϩ T cells are essential for development of diabetes by recognizing ␤-cell antigens in the context of the class II MHC I-A g7 . Involvement of CD8 ϩ T cells has also been extensively documented. 4 -7 Various mechanisms for inducing ␤-cell death have been proposed including a role for Fas/FasL, perforin/granzyme pathway, Rae1-NKG2D interaction, and reactive oxygen species induced by proinflammatory cytokines. 8 -12 A major hurdle in understanding the role of various leukocytes in T1DM is the large and varied time span between peri-insulitis and onset of diabetes (in NOD mice it can be anywhere between 10 to 14 weeks). Moreover, the presence of both CD4 ϩ and CD8 ϩ T cells makes it difficult to dissect the effector pathways used by each to induce islet ␤-cell death. To this end, we have examined an accelerated model of T1DM using the diabetogenic CD4 ϩ T cell, BDC2.5, expressed as a T-cell receptor (TCR) transgene in NOD mice (from here on referred to as BDC T cells). BDC T cells recognize an unidentified islet ␤-cell antigen presented by the I-A g7 class II MHC molecule of NOD mice. 13 Activated BDC T cells transfer diabetes into NOD.scid recipients in a short period of time with reproducible kinetics and incidence.

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Thymic and Postthymic Regulation of Diabetogenic CD8 T Cell Development in TCR Transgenic Nonobese Diabetic (NOD) Mice

Cited by 22 publications

References 33 publications

Autoreactive Diabetogenic T-Cells in NOD Mice Can Efficiently Expand From a Greatly Reduced Precursor Pool

Autoreactive Diabetogenic T-Cells in NOD Mice Can Efficiently Expand From a Greatly Reduced Precursor Pool

Genetic Control of T and B Lymphocyte Activation in Nonobese Diabetic Mice

In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing

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