Making Insulin and Staying Out of Autoimmune Trouble: The Beta-Cell Conundrum

Abstract

Autoimmune type 1 diabetes (T1D) results from the intricate crosstalk of various immune cell types. CD8+ T cells dominate the pro-inflammatory milieu of islet infiltration (insulitis), and are considered as key effectors of beta-cell destruction, through the recognition of MHC Class I-peptide complexes. The pathways generating MHC Class I-restricted antigens in beta cells are poorly documented. Given their specialized insulin secretory function, the associated granule processing and degradation pathways, basal endoplasmic reticulum stress and susceptibility to additional stressors, alternative antigen processing and presentation (APP) pathways are likely to play a significant role in the generation of the beta-cell immunopeptidome. As direct evidence is missing, we here intersect the specificities of beta-cell function and the literature about APP in other cellular models to generate some hypotheses on APPs relevant to beta cells. We further elaborate on the potential role of these pathways in T1D pathogenesis, based on the current knowledge of antigens presented by beta cells. A better understanding of these pathways may pinpoint novel mechanisms amenable to therapeutic targeting to modulate the immunogenicity of beta cells.

The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

“…First, we observed that constitutive proteasome genes ( PSMB5 , PSMB6 and PSMB7 ) remained unchanged in both WT and KO while IFNα-upregulated genes encoding the immunoproteasome ( PSMB8, PSMB9 and PSMB10 ). Second, transporters associated with antigen processing ( TAP1, TAP2 and TAPBP ) and MHC Class Ι ( HLA-A, HLA-B and HLA-C ) were strongly augmented in the WT β-like cells but remained unchanged in the KO(25) (Figure 5, F-I).…”

“…Additionally, the IFNα-induced up-regulation of antigen processing genes, i.e. immunoproteasome ( PSMB8 , PSMB9 ) and peptide transporters ( TAP1 , TAP2 and TAPBP ) were lost, suggesting impairment of the processing and presentation of immunogenic peptides in the TYK2 KO cells(25). It is thus possible that these effects may synergize to inhibit autoimmune responses in vivo to a larger extent than what we observed in vitro using peptide-reactive CD8 + T cells against peptide-pulsed SC-islets (Figure 7).…”

Induction of antigenic immune tolerance to delay type 1 diabetes – challenges for clinical translation

“…Another essential dilemma in ASIT is the antigen(s) required. In T1D, the chief antigens have been robustly identified (including insulin and glutamic acid decarboxylase [GAD]) [49,50]. However, the relative importance of these antigens in driving disease onset and progression is still uncertain, and there is likely inter-individual variation.…”

β-Cell autophagy in the pathogenesis of type 1 diabetes

“…Together, these studies support a crucial role of the lysosome and lysosomal enzymes in driving autoimmunity. Indeed, the putative relevance of defective beta cell autophagy in antigen processing and presentation was recently reviewed [44]. One key point that remains difficult to parse out is whether autophagy defects in the beta cell, or complementary defects in the immune cells play a greater role in the cascade of events leading to T1D.…”