Major histocompatibility complex (MHC) genes, also known as human leukocyte antigen genes (HLA) in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D), Multiple Sclerosis (MS), and Rheumatoid arthritis (RA), among others (Todd and Wicker, 2001;MacKay et al., 2002;Hafler et al., 2007). Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T cell repertoires of the host towards autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development towards a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development towards non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a CD4⁺and CD8⁺T cell-dependent autoimmune process directed against the pancreatic beta cells. CD8⁺T cells play a critical role in the initiation and progression of diabetes, but the specificity and diversity of their antigenic repertoire remain unknown. Here, we define the structure of a peptide mimotope that elicits the proliferation, cytokine secretion, differentiation, and cytotoxicity of a diabetogenic H-2K^d-restricted CD8⁺T cell specificity (NY8.3) that uses a T cell receptor α (TCRα) rearrangement frequently expressed by CD8⁺T cells propagated from the earliest insulitic lesions of NOD mice (Vα17-Jα42 elements, often joined by the N-region sequence M-R-D/E). Stimulation of splenic CD8⁺T cells from single-chain 8.3-TCRβ-transgenic NOD mice with this mimotope leads to preferential expansion of T cells bearing an endogenously derived TCRα chain identical to the one used by their islet-associated CD8⁺T cells, which is also identical to the 8.3-TCRα sequence. Cytotoxicity assays using islet-derived CD8⁺T cell clones from nontransgenic NOD mice as effectors and peptide-pulsed H-2K^d-transfected RMA-S cells as targets indicate that nearly half of the CD8⁺T cells recruited to islets in NOD mice specifically recognize the same peptide/H-2K^dcomplex. This work demonstrates that beta cell-reactive CD8⁺T cells mount a prevalent response against a single peptide/MHC complex and provides one peptide ligand for CD8⁺T cells in autoimmune diabetes.

Cytokines such as IL-1α, IL-1β, and IFN-γ have long been implicated in the pathogenesis of autoimmune diabetes, but the mechanisms through which they promote diabetogenesis remain unclear. Here we show that CD4⁺ T lymphocytes propagated from transgenic nonobese diabetic (NOD) mice expressing the highly diabetogenic, β cell–specific 4.1-T-cell receptor (4.1-TCR) can kill IL-1α–, IL-1β–, and IFN-γ–treated β cells from NOD mice. Untreated NOD β cells and cytokine-treated β cells from Fas-deficient NOD.lpr mice are not targeted by these T cells. Killing of islet cells in vitro was associated with cytokine-induced upregulation of Fas on islet cells and was independent of MHC class II expression. Abrogation of Fas expression in 4.1-TCR–transgenic NOD mice afforded nearly complete protection from diabetes and did not interfere with the development of the transgenic CD4⁺ T cells or with their ability to cause insulitis. In contrast, abrogation of perforin expression did not affect β cell–specific cytotoxicity or the diabetogenic potential of these T cells. These data demonstrate a novel mechanism of action of IL-1α, IL-1β, and IFN-γ in autoimmune diabetes, whereby these cytokines mark β cells for Fas-dependent lysis by autoreactive CD4⁺ T cells.