The selective loss of insulin-producing pancreatic beta cells which occurs in IDDM has been postulated to result from lysis by beta cell-specific cytotoxic T lymphocytes (CTL). CTL typically recognise antigen in the context of MHC class I molecules, which are normally present at low levels on beta cells. However, hyperexpression of class I antigens on islet cells has been observed in the early stages of beta cell destruction in IDDM. Since interferon-gamma (IFN-gamma) is known to increase class I expression on a number of cell types, we have investigated the responses of murine beta cells to this cytokine under various conditions. Two color immunostaining followed by FACS analysis showed that on average, only 14.9 +/- 3.1% of cultured beta cells were class I positive. However, a majority of beta cells could be induced to express class I after 24 hours of IFN-gamma treatment, and maximal induction (80-90% positive) occurred after 48 hours. Importantly, increased class I expression on beta cells could be achieved with very low concentrations of IFN-gamma (1-10 U/ml). Expression of class II MHC was never detected under any of the conditions employed to up-regulate class I. Interestingly, although islet cells were only moderately susceptible to lysis by allospecific CTL, this susceptibility was markedly enhanced by prior exposure of the islets to IFN-gamma. Taken together, these results suggest that beta cells are extremely susceptible to up-regulation of class I MHC molecules by IFN-gamma, and that this property may render these cells particularly susceptible to lysis by autologous class I-restricted CTL. Since enhanced expression of class I frequently accompanies inflammatory responses and viral infections, this property of beta cells may account in part for their selective destruction in IDDM.