In these studies, we have shown that the heme moiety of cyt c is a dominant T cell epitope that induces a large proliferative response in lymph node T cells derived from SJL and B10.A mice when presented on either unfixed or fixed syngeneic APCs. Not only is this vigorous response observed for cyt c-primed T cell populations but also for populations obtained from naive SJL or B10.A mice. The reactivity to the heme moiety falls under strict MHC restriction, in that it is present only in murine strains bearing either the I-Ak or I-As molecule and can be blocked by antibodies specific for these class II molecules. Therefore, these findings require that the current models describing the nature of T cell epitopes be extended to include nonpeptide molecules. Furthermore, as the heme moiety is ubiquitous throughout the organism, although sequestered within proteins, the existence of heme-reactive T cell populations in unprimed animals provides another example of the existence of self-reactive T cell clones.