MHC Class II Polymorphisms, Autoreactive T-Cells, and Autoimmunity

Abstract

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, and rheumatoid arthritis, among others (1-3). 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 toward autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development toward a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development toward 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.

Keywords: MHC class II; T regulatory cells; autoimmune diseases; autoreactive T cells; resistance genes; susceptibility genes; type 1 diabetes.

Figure 1

MHC class II polymorphisms afford autoimmune disease resistance through shaping the T cell and Treg repertoire. MHC class II molecules that afford disease risk allow the escape of pathogenic autoreactive T cells from central tolerance, while protective MHC class II molecules confer disease resistance through promoting negative selection as well as autoreactive Treg development. We propose that these processes are governed by the affinity/avidity with which pMHCs are bound by TCRs. Disease-protective pMHC interact with MHC-promiscuous, autoreactive thymocytes with increased affinity/avidity (top and middle panels), leading to enhanced negative selection and agonist selection of Tregs, which then dampen the autoimmune response through various mechanisms. In the bottom scenario, low affinity/avidity interaction between pMHC and autoreactive TCRs leads to defective negative selection and Treg development, with the net result of autoimmunity.

Figure 2

Protective MHC class II molecules mediate central and peripheral tolerance by targeting MHC-promiscuous autoreactive TCRs. Positive selection on I-A^g7 in the thymic cortex determines the MHC restriction of thymocytes (A). In the absence of protective MHC molecules, negative selection is defective and fail to purge the repertoire of pathogenic autoreactive thymocytes (not shown) (B). Transgenic expression of disease-protective MHC class II molecules on dendritic cells leads to enhanced negative selection and clonal anergy of autoreactive, MHC-promiscuous thymocytes, and promotes autoreactive Treg differentiation and functional development (C). Thymic derived Tregs then exit into the periphery and suppress the activation of pathogenic T cells by directly acting on autoantigen-loaded APCs. This step does not require protective MHC class II molecules, although a role of protective MHC class II molecules, expressed on peripheral APCs, in perpetuating autoreactive Tregs or enhancing their homeostasis cannot be ruled out (D).