Non-Genetically Encoded Epitopes Are Relevant Targets in Autoimmune Diabetes

Abstract

Islet antigen reactive T cells play a key role in promoting beta cell destruction in type 1 diabetes (T1D). Self-reactive T cells are typically deleted through negative selection in the thymus or deviated to a regulatory phenotype. Nevertheless, those processes are imperfect such that even healthy individuals have a reservoir of potentially autoreactive T cells. What remains less clear is how tolerance is lost to insulin and other beta cell specific antigens. Islet autoantibodies, the best predictor of disease risk, are known to recognize classical antigens such as proinsulin, GAD65, IA-2, and ZnT8. These antibodies are thought to be supported by the expansion of autoreactive CD4⁺ T cells that recognize these same antigenic targets. However, recent studies have identified new classes of non-genetically encoded epitopes that may reflect crucial gaps in central and peripheral tolerance. Notably, some of these specificities, including epitopes from enzymatically post-translationally modified antigens and hybrid insulin peptides, are present at relatively high frequencies in the peripheral blood of patients with T1D. We conclude that CD4⁺ T cells that recognize non-genetically encoded epitopes are likely to make an important contribution to the progression of islet autoimmunity in T1D. We further propose that these classes of neo-epitopes should be considered as possible targets for strategies to induce antigen specific tolerance.

Keywords: T cell; neo-antigen; post-translational modification; selection; type 1 diabetes.

Figure 1

Central and peripheral tolerance. Central tolerance occurs in the thymus and relies on self-antigen expression on medullary thymic epithelial cells (mTEC) under regulation of the transcription factor AIRE. CD4⁺ T cells that recognize self-antigens in the context of HLA class II proteins undergo positive or negative selection. The selection process is based on the nature of the interaction between TCR and HLA-peptide complex. T cells that are positively selected go on to populate the periphery where they are controlled by peripheral tolerance mechanisms acting directly on the self-reactive T cells (intrinsic) or indirectly via additional cells (extrinsic). Figure created with BioRender.com.

Figure 2

Formation of neo-antigens and epitopes. An undetermined stress event (a) combines with the beta cell’s unique metabolism and vulnerability to cellular and environmental stresses, leading to a cascade of deleterious events. Consequently, tissue specific proteins (b) are altered, leading to the formation of immunogenic neoepitopes (c) via enzymatic catalyzed pathways such as citrullination and deamidation, or biochemical reformation of reactive sidechains by processes such as oxidation. (d) Neoepitopes can also arise due to events during transcription and translation, producing alternatively spliced (AS) peptide junctions or defective ribosomal products (DRiPs). These neoepitopes can be presented by antigen presenting cells (APCs) resulting in autoreactive T cell responses.