Antigen processing and presentation in beta cells: what T cells see in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease ultimately mediated by CD8+ T cells recognizing peptide-HLA Class I complexes on the surface of beta cells, leading to their cytotoxic lysis. Despite this notion, little information is available about the peptides that are naturally processed and presented by beta cells. The identification of these peptides by immunopeptidomics revealed that most of them are derived from proteins of the insulin secretory granules and comprise neo-antigens generated by alternative mRNA splicing and transpeptidation (Gonzalez-Duque, Cell Metab 2018). Moreover, inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of HLA Class I expression. However, circulating CD8+ T cells recognizing these peptides displayed similar frequencies and a largely naïve phenotype in T1D and healthy donors. In line with our previous report on islet epitopes already described (Culina, Sci Immunol 2018), this phenotype suggests no active involvement in the autoimmune process and may reflect sequestration of the pathogenic fraction in the target organ. Indeed, these same CD8+ T cells are found selectively enriched in the pancreas of T1D patients. Thus, a universal state of ‘benign’ islet autoimmunity is present in all individuals and is imprinted in the thymus, where the ectopic presentation of islet epitopes does not significantly impact on the burden of peripheral autoreactive CD8+ T cells. Understanding the mechanisms that lead to the switch from this benign autoimmunity to T1D is key to understand disease pathogenesis, to develop early biomarkers of T1D progression, and to devise therapeutic strategies to prevent autoimmune progression. One such mechanism may be the loss of immune ignorance once beta cells become visible to autoimmune CD8+ T cells, by increasing their peptide-HLA display in the inflammatory milieu of the T1D pancreas. We propose that T1D may be a disease of autoimmunity and of the target beta cell itself.