Self-antigens, benign autoimmunity and type 1 diabetes: a beta-cell and T-cell perspective

Abstract

Purpose of reviewRecent work using immunopeptidomics and deconvolution of the antigenic reactivity of islet-infiltrating CD8þ T cells has expanded our knowledge about the autoimmune target epitopes of type 1 diabetes. The stem-like properties of autoimmune CD8þ T cells have also been described. We here propose a possible link between these findings. Recent findingsWeak major histocompatibility complex (MHC)-binding epitopes list among the major targets of human islet-infiltrating CD8þ T cells, likely resulting in low peptide-MHC presentation that delivers weak T-cell receptor (TCR) signals, especially in the face of low-affinity autoimmune TCRs. These weak TCR signals may favor the maintenance of the partially differentiated stem-like phenotype recently described for islet-reactive CD8þ T cells in the blood and pancreatic lymph nodes. These weak TCR signals may also be physiological, reflecting the need for self-peptide-MHC contacts to maintain homeostatic T-cell survival and proliferation. These features may underlie the universal state of benign autoimmunity that we recently described, which is characterized by islet-reactive, na € ive-like CD8þ T cells circulating in all individuals.

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

“…First, our work focused on predicted HLA-I ligands, and the datasets used to train prediction algorithms are mostly derived from viral and tumor immunology studies. While in these studies HLA-I binding is a good predictor of T-cell immunogenicity, it likely underestimates the number of potential epitopes in the case of autoimmunity 43 , possibly reflecting a bias imposed by thymic T-cell deletion. Predicted non-binders may hide additional immunogenic peptides, as recently demonstrated for cancer neo-epitopes 66,67 .…”

“…The INS DRiP case is noteworthy, as it has been confirmed as a relevant T-cell antigen targeted by islet-infiltrating CD8 + T-cells 32 . The short-lived and unstable nature of INS DRiP and the fact that its presentation is enhanced by IFN-γ but not IFN-α 42 may explain this discrepancy, emphasizing the need for complementary antigen identification strategies 43 . The proteasome-independent generation of some peptides identified may reflect their processing in other cell compartments.…”

Insulitis in human type 1 diabetes: lessons from an enigmatic lesion

“…In particular, CD8+ T-cells are induced to kill target cells by mechanisms involving recognition of relevant (“non-self”) peptides which are processed and displayed on MHC class I molecules. 67 , 68 Importantly, a hallmark feature of type 1 diabetes is the hyper-expression of MHC-I on islet cells which are induced to reach levels well beyond those found in the islets of control subjects without diabetes. 69 Elution of the peptides that are displayed on islet cell MHC-I under these conditions suggest that these could be involved in immune cell targeting, especially as they are likely to become displayed at increased intensity as a result of the MHC-I hyper-expression.…”

Epitope-based precision immunotherapy of Type 1 diabetes

“…Studies using MHC multimers also reported that autoantigen-specific T cells are found in the circulation of healthy individuals, typically with similar frequencies, 40 , 60 , 62 , 63 which suggests that negative selection in the thymus may be limited to the highest affinity autoreactive T cells in all individuals, and that in T1D patients, it is mainly a defective regulation of the remaining T cells that allows them to be activated and become pathogenic. 64 Beyond detecting those T cells, it may be more important to determine their phenotype (i.e., whether these circulating T cells are more activated and antigen-experienced). Again, in MHC multimer-based analyses of circulating autoreactive CD8+ T cells comparing control and T1D donors, differences are difficult to pinpoint.…”