GAD65- and proinsulin-specific CD4+ T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects

Autoreactive T cells in type 1 diabetes

“…These proinsulin and GAD65 TCR sequences were found in the PLN of some T1D donors. CD4 + T cells targeting the GAD65 555-567 epitope were described in peripheral blood of patients (68,184).…”

Immunology of β-Cell Destruction

“…The immunogenic epitopes are selected among putative immunodominant regions within the multiple diabetes-related islet autoantigens. Many of these studies report a higher frequency of islet-specific self-reactive T cells in T1D patients than in control subjects, when T cells are detected by either functional tests of antigen-induced proliferative [96] and cytokine-secretive response [91,102,316,317] or tetramer staining [101,318,319].…”

“…CD8+ and CD4+ T cells from T1D patients target a wide array of epitopes within GAD65 molecule [92,316,[318][319][320][321][322], insulin and proinsulin [91,[323][324][325], IA-2 [316,317,326], IGRP [323,327,328], I-A2b [327,328], islet amyloid polypeptide (IAPP) [327][328][329], and glial fibrillary acidic protein (GFAP) [328] as comprehensively summarized in a review updated to the end of 2006 [330]. More recently, a few more epitopes have been described, as GAD536-545 [316], other IGRP fragments, among which IGRP 211-219 and 222-230 [331], and several novel insulinand proinsulin-derived peptides targeted by CD8+ [323,332,333] and CD4+ T cells [334].…”

“…Longitudinal studies investigating DC and T cells in at-risk subjects are lacking. Some reports have found poor in vitro maturation and pro-in ammatory cytokine response in DC from children at genetic risk for TID [389,390] and a number of attested T-cell responses from PBMC of at-risk subjects toward islet-specific autoantigens GAD65 [318,319] and insulin/proinsulin [318,328]. Finally, increased chemokines, such as CXCl10 [354] and adhesion molecules [356], have been detected in the plasma of at-risk individuals; more recently, in three at-risk subjects followed until diagnosis these alterations were present years before the clinical onset [367].…”

The Cross-Regulatory Relationship Between Human Dendritic and Regulatory T Cells and its Role in Type 1 Diabetes Mellitus

“…These T cells may then escape into the periphery [2,3]. Evidence for this cascade of events emerged from the finding that islet antigen-specific CD4 + T cells have been detected in the periphery of at-risk individuals and diabetic subjects [4,5].…”