Review articleAutoreactive T cells in human type 1 diabetes☆
Section snippets
T-cell targets and epitopes
The considerable advances in autoimmune serology during 1975 to 1991 led to the unequivocal identification of three major islet autoantibody specificities, targeted against insulin, glutamic acid decarboxylase (GAD), and the islet tyrosine phosphatase, IA-2 [1], [2], [3]. Most T-cell epitope studies have focused on these three autoantigens—the existence of class-switched IgG autoantibodies strongly implies the influence of T-cell help—and this article discusses the evidence that T cells
Lessons from autoreactive CD4 T-cell clones in type 1 diabetes
Despite the reservations expressed previously, T-cell cloning remains one of the more enduring and successful approaches to epitope identification. Moreover, it offers the real possibility of ascertaining the epitopes targeted during disease development (although few cloning programs have used prediabetic subjects) and providing functional information regarding the responder T cells. On the negative side, cloning is laborious, frequently unsuccessful, and likely to be biased toward selection of
Lessons from autoreactive CD8 T-cell clones in type 1 diabetes
There is a considerable logic behind the need for studies on CD8 T-cell reactivity in T1D. CD8 T cells have potent cytotoxic potential and are the likely candidates for delivering the final toxic blow to β cells. In addition, they are well represented in the insulitic lesion and surrounded by abundant ligand in the form of class I MHC-expressing islet cells [38]. Moreover, recent evidence indicates that specific class I HLA molecules (HLA-A2.1 and HLA-A24) are associated with an increased risk
Antigen-specific regulatory T cells
Although most islet antigen-specific TCCs have been isolated from individuals with T1D, several studies have hinted at the presence of such T cells in individuals without the disease [33], [43], [44]. It is proposed that, in healthy individuals, these cells are held in check by several mechanisms, including the action of regulatory T cells, and that T1D arises in part because of a failure of these regulatory pathways. Against this background, several studies have pointed to a dysfunctional
Detection of autoreactive T cells ex vivo
The studies discussed previously highlight the importance of epitope discovery, which provides the ammunition for what is considered by many to be the real battle—that is, to enumerate and characterize islet autoreactive T cells directly ex vivo. Ideal assay characteristics include the ability to accurately quantify the frequency of antigen-specific T cells at a high level of sensitivity and specificity and the capacity to perform analysis of the quality of the response, through cytokine and
Summary
This systematic review of the information from studies on human autoreactive T cells is highly instructive. Studies on T-cell targets reveal the potential for disease-related and HLA allele-related peptide epitopes to be identified with current technology. The consistent lack of cloning success from nondiabetic control subjects, coupled with other studies on T-cell function [25], provides strong evidence that circulating autoreactive T cells are available for analysis in the peripheral blood of
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Mark Peakman is a Diabetes UK Senior Clinical Research Fellow. Work from the authors' laboratory alluded to in this article was supported by Diabetes UK and The Wellcome Trust.