Type 1 Interferons Potentiate Human CD8+ T-Cell Cytotoxicity Through a STAT4-and Granzyme B-Dependent Pathway

Events defining the progression to human type 1 diabetes (T1D) have remained elusive owing to the complex interaction between genetics, the immune system, and the environment. Type 1 interferons (T1-IFN) are known to be a constituent of the autoinflammatory milieu within the pancreas of patients with T1D. However, the capacity of IFN alpha/beta to modulate human activated autoreactive CD8(+) T-cell (cytotoxic T lymphocyte) responses within the islets of patients with T1D has not been investigated. Here, we engineer human beta-cell-specific cytotoxic T lymphocytes and demonstrate that T1-IFN augments cytotoxicity by inducing rapid phosphorylation of STAT4, resulting in direct binding at the granzyme B promoter within 2 h of exposure. The current findings provide novel insights concerning the regulation of effector function by T1-IFN in human antigen-experienced CD8(+) T cells and provide a mechanism by which the presence of T1-IFN potentiates diabetogenicity within the autoimmune islet.