Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes

Abstract

T cell epitopes represent the molecular code words through which the adaptive immune system communicates. In the context of a T cell-mediated autoimmune disease such as type 1 diabetes, CD4 and CD8 T cell recognition of islet autoantigenic epitopes is a key step in the autoimmune cascade. Epitope recognition takes place during the generation of tolerance, during its loss as the disease process is initiated, and during epitope spreading as islet cell damage is perpetuated. Epitope recognition is also a potentially critical element in therapeutic interventions such as antigen-specific immunotherapy. T cell epitope discovery, therefore, is an important component of type 1 diabetes research, in both human and murine models. With this in mind, in this review we present a comprehensive guide to epitopes that have been identified as T cell targets in autoimmune diabetes. Targets of both CD4 and CD8 T cells are listed for human type 1 diabetes, for humanized [human leucocyte antigen (HLA)-transgenic] mouse models, and for the major spontaneous disease model, the non-obese diabetic (NOD) mouse. Importantly, for each epitope we provide an analysis of the relative stringency with which it has been identified, including whether recognition is spontaneous or induced and whether there is evidence that the epitope is generated from the native protein by natural antigen processing. This analysis provides an important resource for investigating diabetes pathogenesis, for developing antigen-specific therapies, and for developing strategies for T cell monitoring during disease development and therapeutic intervention.

Fig. 1

Pie charts showing the antigenic distribution of (a) CD4 and (b) CD8 T cell epitopes in autoimmune diabetes in humans and mice. Data used are from Tables 1–4. For the sake of clarity, the single epitope of ICA69 is not shown in the pie charts in (a).

Fig. 2

Representation of linear sequence and location of CD4 T cell epitopes of the major islet autoantigens preproinsulin, GAD65, and IA-2 in human type 1 diabetes. GAD65 and IA-2 are drawn to the same scale, whereas preproinsulin is enlarged three-fold for clarity. Epitopes shown are from Table 1. Where data exist that show an epitope to be unambiguously restricted by a particular HLA class II molecule, this is shown with shading, where black = HLA-DQ8; diagonal stripes = HLA-DR3 (DRB1*0301), and grey = HLA-DR4 (DRB1*0401). All other epitopes are shown as white boxes. TM = transmembrane.