Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Abstract

Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-␥ and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.T ype I diabetes mellitus in humans is an autoimmune disease that results from the selective destruction of pancreatic ␤-cells by T cells (1, 2). The nonobese diabetic (NOD) mouse develops spontaneous autoimmune diabetes that shares many characteristics with the human disease (1, 3, 4). The principal islet cell antigens targeted by autoreactive T cells in NOD mice include insulin (5), glutamic acid decarboxylase 65 (GAD65) (6), 65-kDa heat shock protein (7), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (8). Among these, T cell responses to GAD65 and insulin are detected early preceding the onset of clinical disease (3-5 weeks of age in the NOD mouse) (9-11). This result has led to the speculation that GAD65 may be among the first autoantigens targeted by T cells that initiate the diabetes pathogenesis.The hypothesis for a pathogenic role of GAD65 is supported by a GAD65-specific T cell clone that induces insulitis and diabetes upon adoptive transfer (12) and by the finding that prevention of GAD65 expression in the pancreatic islets by GAD antisense cDNA prevented diabetes (13). In contrast, induction of deletional T cell tolerance by widespread expression of a GAD65 transgene did not alter diabetes pathogenesis (14) but exacerbated the disease (15). In addition, several GAD65-specific T cell clones, lines, and T cell antigen receptor (TCR) transgenic mice were not pathogenic and exhibited a diabetesdelaying capacity (16-18). Thus, it appears that GAD65 may not be a required initiating antigen for diabetes pathogenesis but rather induces a protective response.To further examine the functions of GAD65-reactive T cells in the pathogenesis of diabetes, we have ge...

Reovirus Delays Diabetes Onset but Does Not Prevent Insulitis in Nonobese Diabetic Mice

“…Therefore, release of ␤-cell antigens as a by-product of reovirus infection may lead to active tolerance by induction of regulatory T cells. Of note, blockade of diabetes in NOD mice (11). Similar to the effects of reovirus infection reported here, CVB infection of newborn NOD mice blocks the development of diabetes (32).…”

Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein-Reactive CD4+ T Cells in Human Subjects

“…The detection of IGRP-specific T cells in both healthy and T1D subjects and the secretion of IL-10 by these cells in this study suggest that IGRP-specific T cells could have a similar regulatory role in humans. However, it should be noted that CD4 ϩ GAD65-reactive T cells have been demonstrated to have both pathogenic and regulatory roles in T cell transfer experiments in murine models (35)(36)(37). Our group and others (24,38) have detected GAD65-reactive T cells in both healthy and T1D subjects.…”

“…8 -27 ) and p29 (IGRP 225-244 ) have a DR0301 binding motif, and peptides p3 (IGRP [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ) and p31 (IGRP 241-260 ) have a DR0401 binding motif.…”

Peptides and Proteins for Treatment and Suppression of Type 1 Diabetes

“…A shift into the Th2 phenotype could be maintained for a long time, and the capacity of different epitopes to induce Th2 cells depended on the frequency of the clonotype T cells (Tisch et al, 1999). P 208-217 peptide from the GAD sequence (Table 1) suppressed the progress of T1D in NOD mice due to deviation of T-cell differentiation from inflammatory to regulatory cells (Kim et al, 2004;McDevitt, 2004;Tisch et al, 1998). Different GAD65 epitopes are recognized by I-A g7 and I-A g7.PD , and the selectivity of recognition is due to the specificity of MHC-II for a certain epitope as well as the specificity of TCR recognition of the MHC-peptide complex by a subpopulation of T cells (Chao et al, 1999).…”