The T Cell Response to Glutamic Acid Decarboxylase 65 in T Cell Receptor Transgenic NOD Mice

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

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Assessment of CD4+ T Cell Responses to Glutamic Acid Decarboxylase 65 Using DQ8 Tetramers Reveals a Pathogenic Role of GAD65 121–140 and GAD65 250–266 in T1D Development

PLoS ONE ◽

10.1371/journal.pone.0112882 ◽

2014 ◽

Vol 9 (11) ◽

pp. e112882 ◽

Cited By ~ 21

Author(s):

I-Ting Chow ◽

Junbao Yang ◽

Theresa J. Gates ◽

Eddie A. James ◽

Duy T. Mai ◽

...

Keyword(s):

T Cell ◽

Glutamic Acid ◽

Glutamic Acid Decarboxylase ◽

T Cell Responses ◽

Cd4 T Cell ◽

Acid Decarboxylase ◽

Pathogenic Role ◽

Cell Responses ◽

Glutamic Acid Decarboxylase 65

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CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals

Blood ◽

10.1182/blood-2007-04-079863 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2053-2061 ◽

Cited By ~ 25

Author(s):

Laura Crompton ◽

Naeem Khan ◽

Rajiv Khanna ◽

Laxman Nayak ◽

Paul A. H. Moss

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Response ◽

Cd4 T Cells ◽

Clonal Selection ◽

Cell Receptor ◽

T Cell Response ◽

Cd4 T Cell ◽

Extreme Conservation

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.

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