Langerhans cells (LC) are APC that reside at the barrier surfaces. Mice expressing an OVA peptide in the epidermis (K14-OVAp) were used to study CD8(+) T cell responses to an epidermal self-Ag. Earlier results suggested that LC were the predominant APC, inducing a robust T cell response and autoimmunity. In this study, we used a whole protein model system, the K14-mOVA mouse, in which a transmembrane form of OVA was expressed in keratinocytes. In contrast to K14-OVAp mice, T cells in K14-mOVA mice were activated, but did not expand and instead died by apoptosis. Furthermore, in double-transgenic mice expressing both mOVA and OVAp, robust OT-I expansion occurred, indicating that tolerance to this Ag is not dominant and was due to lack of activating signals. We sought to identify the relevant APC in K14 mice using bone marrow chimeras and found that radioresistant cells (presumably LC) were able to cross-present the OVA Ag from keratinocytes to naive T cells in the lymph node. However, use of LC-deficient mice indicated that LC were not required for the expansion of OT-I in K14-OVAp or the deletion of OT-I in K14-mOVA mice. These data suggest that radioresistant non-LC present self-Ag in K14-OVAp mice and drive a robust CD8 T cell response.