In vivo maturation of allo-specific CD8 CTL and prevention of lupus-like graft-versus-host disease is critically dependent on T cell signaling through the TNF p75 receptor but not the TNF p55 receptor.

A third signal is required for maturation of effector CD8 CTL in addition to TCR and CD28 engagement. Inflammatory cytokines can provide a third signal; however, in nonpathogen settings (i.e., antitumor responses), the identity of the third signal is not clear. A useful model for in vivo CD8 CTL in the absence of exogenous pathogens is the alloantigen-driven parent-into F1 model of acute graft-versus-host disease (GVHD) characterized by a strong TNF-dependent donor antihost CD8 CTL T cell response. To determine whether TNF acts directly on donor T cells in a signal 3 manner, F1 mice received TNFR 1 (p55) knockout (KO) and/or TNFR 2 (p75) KO donor T cells. Donor p75 KO but not p55KO donor T cells failed to induce acute GVHD phenotype and instead induced a lupus-like chronic GVHD both short and long term because of quantitative and qualitative donor T cell defects, that is, reduced perforin, IFN-γ, and TNF production. Transfer of mixed or matched purified CD4 and CD8 T cells from wild type or p75KO donors demonstrated that optimal CTL maturation required p75 signaling in both CD4 and CD8 T cells. Despite defective p75KO CD4 help for CD8 CTL, p75KO CD4 help for B cells and autoimmunity was intact. These results provide a mechanism by which impaired CD8 CTL could contribute to reduced antiviral and antitumor responses and autoimmunity reported in patients receiving TNF blockers. Our results support the idea that selective p55 blockade may be beneficial by reducing inflammation without compromising CD8 CTL.