Soluble HLA Class I Is Released From Human β-Cells Following Exposure to Interferons.

Abstract

HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T cells during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing β-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a "halo." We hypothesized that this halo may reflect the diffusion of soluble forms of HLA-I (sHLA-I) from the islets to the surrounding pancreatic parenchyma. To verify this, we assessed the expression of total, cell surface, and sHLA-I in β-cell lines and isolated human islets after treatment with interferon-α (IFN-α) and IFN-γ. Consistent with the expression patterns of HLA-I in situ, the β-cell lines and cultured human islets dramatically upregulated total and surface HLA-I when exposed to IFNs. Concomitantly, sHLA-I release was significantly increased. HLA-I released within extracellular vesicles and cleaved forms of HLA-I did not significantly contribute to the sHLA-I pool. Rather, IFNs upregulated mRNA splice variants lacking the transmembrane domain. Our findings suggest that β-cells respond to IFNs by upregulating cell-associated and soluble forms of HLA-I. Soluble HLA-I may play a role in modulating islet inflammation during the autoimmune attack. Hyperexpression of cell-associated HLA class I (HLA-I) induced by interferons is a hallmark feature of the residual insulin-containing pancreatic islets of people with type 1 diabetes. Soluble forms of HLA-I have also been described and are increased in the blood of individuals with viral infections and autoimmune disease, including type 1 diabetes. We assessed whether β-cells release soluble HLA-I (sHLA-I) in response to interferons. We confirm that human β-cells release significant levels of sHLA-I, demonstrate that this increases after interferon exposure, and define the release mechanism. We propose that sHLA-I may affect the activity of infiltrating CD8+ T cells in type 1 diabetes.