To examine the effects of aberrant expression of class II major histocompatibility complex (MHC) proteins on tolerance development, transgenic mice expressing the I-A(d) genes under control of the pancreatic elastase promoter were produced. Such transgenic mice express I-A(d) exclusively on exocrine pancreas, without expression in thymus or by lymphocytes. No spontaneous development of autoimmune reactivity toward exocrine pancreas was found in transgene-expressing mice of an H-2b background even though such mice could produce in vitro allogeneic responses against I-A(d). When T cells from nontransgenic H-2(b) mice as well as transgenic H-2b mice were activated in vitro by I-A(d) allogeneic stimulator cells and transferred to transgenic mice, an intense, destructive lymphocytic infiltrate specific for exocrine pancreas developed. These findings suggest that aberrant class II MHC expression alone may not trigger autoimmune reactions. Rather, the unresponsiveness to allogeneic class II MHC may result from the inability of exocrine pancreas to initiate primary responses by T cells.