Title

Shaping and optimizing CD8 T cell responses through CD137 and CD134 dual costimulation

Date of Completion

January 2007

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

The TNFR superfamily members 4-1 BB (CD137) and OX40 (CD134) are costimulatory molecules that promote CD8 and CD4 T cell responses, and they share similar features such as surface expression on activated T cells, adaptor molecule usage, and signaling pathways. However, concomitant therapeutic administration of agonistic anti-CD137 and -CD134 mAbs profoundly boosted antigen-specific CD8 T cell responses, and importantly, mediated rejection of established tumors, which suggest that CD137 and CD134 dual costimulation may be efficacious for cancer immunotherapy. The role of CD4 help was dispensable for clonal expansion and effector function of dual costimulated CD8 T cells. Direct CD137 signaling on CD8 T cells was crucial for clonal expansion and accumulation of effector cells. In particular, it was noticed that a subpopulation of effectors possessed super effector capabilities since they concomitantly produced high levels of IFN-γ and TNF. CD134 costimulation promoted this super effector function, which was linked to CD137 signaling implying that these two different costimulatory pathways are interdependent. Dual costimulation enhanced survivability of specific CD8 T cells rather than increased successive rounds of cellular division, which was thought to involve the common gamma (γc) cytokine family members such as CD25 and CD127. This idea was supported by demonstrating that dual costimulated CD8 T cells induced substantial increases of CD25 and CD127 expression compared to single costimulators. Importantly, dual costimulation also directed CD8 T cell and super effector survival in an IL-7 dependent manner. In general, the dual costimulated cells were sensitive to the intrinsic death pathway, but resistant to Fasbased death. In part, this was explained by the NF-κB pathway, which played an important role in different aspects of survival. For example, specific NF-κB inhibitors induced cell death even in the presence of survival cytokines, suggesting that NF-κB signaling was critical for induced cell survivability, and that death programming overrides cytokine-induced cell survival. Thus, the dual combination of CD137 and CD134 mediates an important bridge between the γc cytokine family and the NF-κB pathway, and supports an efficacious approach of using the TNFR superfamily members for cancer immunotherapy and for vaccine development. ^