Effective antigen presentation and survival requirements for tumor-specific CD8(+) T cell in vivo

The overall goal of this thesis work is to understand the antigen presentation and survival requirements for tumor-specific CD8+ T cells in vivo.; To examine a role for host MHC in tumor antigen-presentation, naive TCR transgenic CD8+ T cells were transferred into TCRα −/− recipient mice having deficient or irrelevant class I MHC expression. With a single T cell transfer, recipients were unable to reject a specific tumor challenge. However, lack of rejection was not due to failed T cell priming. Rather, the lifespan of both naive and primed T cells was found to be significantly shortened in these recipients. When T cells were repeatedly transferred to compensate for the decreased half-life, tumor rejection was restored. These results suggest that direct antigen presentation by tumor cells can be sufficient to prime tumor-reactive CD8+ T cells, but that appropriate host class I MHC molecules remain vital for supporting CD8+ T cell survival.; To determine whether epitope spreading can occur during an anti-tumor immune response, two defined class I MHC-binding peptides in the P815 tumor model were utilized. We observed that immunization against a single tumor peptide, P1A, followed by rejection of a P1A+ tumor, subsequently yielded CTL activity and tumor protection against a P1A − tumor variant. P1A immunized mice that subsequently rejected tumor challenge developed CTL against a second defined epitope, P1E. These results indicate that, as for class II-restricted peptides in autoimmune disease, epitope spreading can occur for class I-restricted peptides during tumor rejection.; Host expression of the class I MHC molecules involved in thymic positive selection, on either bone-marrow- or non-bone marrow-derived cells, is required for the survival of naive and activated peripheral CD8+ T cells. This requirement can be overcome by elimination of Fas signaling on T cells. However, neither elimination of FasL by the T cells nor over-expression of Bcl-x_L by the T cells could overcome the requirement for appropriate host class I MHC expression for T cell survival. Neither CD28 expression by CD8+ T cells nor ICAM-1 expression by the host is required for T cell survival.