What the HLA-I! – Classical and non-classical HLA Class I and their potential roles in type 1 diabetes

Purpose of review: Hyperexpression of classical HLA class I (HLA-I) molecules in insulincontaining islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology. Recent Findings: Evidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein level in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells. Summary: Non-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B, and select T cells the non-classical HLA-I proteins will reduce the non-specific bystander effects of inflammation, whilst at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.