CD8+ cytotoxic T lymphocyte tolerance and immunity

Cytotoxic T lymphocytes (CTLs) represent a subset of lymphocytes that are important in providing effective immune responses in the host. Understanding the molecular mechanisms underlying CTL immunity is relevant for autoimmune diseases, transplantation and tumor immunity. This thesis investigates some of the many factors that influence the induction of CTL tolerance versus immunity. T cell deletion is critical for the homeostatic downregulation of responses following CTL activation and is also one mechanism by which T cell tolerance is induced. In one study presented in this thesis, the contribution of two surface receptors, TNF receptor 1 (TNFR1) and CD95 to CTL deletion was evaluated. It was found that T cell deletion proceeded unimpaired in mice genetically deficient in both TNFR1 and CD95 under all but one condition examined using a lymphocytic choriomeningitis virus-based system. In a second study, the impact of tumor growth on tumor-specific T cells was examined in a murine model for insulinoma. Surprisingly, in this in vivo model, tumor growth favored CTL immunity rather than tolerance, thus shedding light on factors that influence the induction of T cell tolerance versus immunity. In the final study, the role of a recently identified tumor necrosis factor (TNF) superfamily member, receptor activator of NF-κB ligand (RANKL), in the activation of antiviral immune responses was evaluated. Using gene-deficient mice, it was found that RANKL was necessary for generating efficient CTL responses in response to viral immunization. Cooperation between RANKL and another TNF superfamily molecule, CD40L, was also revealed for the activation of virus-specific CTLs. The studies in this thesis define conditions under which TNFR1 and CD95 cooperate to mediate T cell deletion, characterize a tumor model where T cell tolerance does not occur and immunotherapy elicits potent antitumor CTL activity, and present RANKL as a novel positive regulator of CTL responses. Together, these results contribute to the understanding of factors that regulate CD8 + CTL tolerance versus immunity.