HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of islet β-Cells from Donors with Type 1 Diabetes

Abstract

Type 1 diabetes studies consistently generate data showing islet β-cell dysfunction and T-cell mediated anti-β-cell specific autoimmunity. To explore the pathogenesis, we interrogated the β-cell transcriptomes from donors with and without type 1 diabetes using both bulk-sorted and single β-cells. Consistent with immunohistological studies, β-cells from donors with type 1 diabetes displayed increased Class I transcripts and associated mRNA species. These β-cells also expressed mRNA for Class II and Class II antigen presentation pathway components, but lacked macrophage marker, CD68. Immunohistological study of three independent recent-onset type 1 diabetic donor cohorts showed Class II protein and its transcriptional regulator Class II major histocompatibility complex trans-activator (CIITA) protein expressed by a subset of insulin+ CD68- β-cells, specifically found in islets with lymphocytic infiltrates. β-cell surface expression of HLA Class II was detected on a portion of CD45-insulin+ β-cells from donors with type 1 diabetes by immunofluorescence and flow cytometry. Our data demonstrate that pancreatic β-cells from donors with type 1 diabetes express Class II molecules on selected cells with other key genes in those pathways and inflammation-associated genes. β-cell expression of Class II molecules suggests that β-cells may interact directly with islet-infiltrating CD4+ T-cells, and may play an immunopathogenic role.