TRAF proteins and their role in T cell effector function and homeostasis

TNF-receptor associated factor (TRAF) 2 integrates multiple TNF-family signaling pathways in T cells making it a unifying target for immunomodulation based on co-stimulation. This thesis examines the role of TRAF2 in T cell effector responses towards allografts in T cell specific TRAF2 knockout (TRAF2TKO) mice. TRAF2TKO mice permanently accepted the majority of full MHC-mismatched islet allografts without exogenous immunosuppression. Further, rejection of vascular heterotopic heart and skin allografts was delayed. Without TRAF2, CD4+ T cells exhibited reduced proliferation and an altered T cell activation profile correlating with reduced NF-κB and JNK activation. Thus CD4+ T cells require a TRAF2-NF-κB and TRAF2-JNK signalling cascade for activation. Under specific polarizing conditions TRAF2TKO CD4+ T cells more readily converted to a Th2 and Treg phenotype but exhibited impaired Th17 effector differentiation highlighting a role for TRAF2 in T cell effector differentiation. The impaired alloresponse of TRAF2TKO mice was confined to the effector (CD25-) compartment as depletion of CD25+ Tregs did not restore alloresponses to control levels both in vitro and in vivo. Whilst T cell survival and peripheral turnover were unchanged by loss of TRAF2, TRAF2TKO CD4+ T cells failed to persist in a lymphopenic environment, likely contributing to long-term allograft survival in RAG-/- mice receiving TRAF2TKO CD4+ T cells. Phenotypic analysis of T cell subsets in TRAF2TKO mice revealed striking reductions in IL-15 dependent T cell populations: CD8+ effector-memory, CD8+ central-memory, and NKT cells. The loss of IL-15 dependent T cell populations was mechanistically linked to an inability to respond to physiological levels of IL-15. Further, TRAF2TKO mice exhibited reduced CD4+ effector-memory and central-memory T cells, a possible consequence from impaired IL-15 responses. TRAF2TKO CD8+ central-memory and NKT cells were rescued by a super-physiological in vivo boost of IL-15 and exhibited control levels of IL-15 signalling components indicating that loss of TRAF2 does not abolish IL-15 responses but modulates IL-15 sensitivity in vivo. Therefore, targeting the TRAF2 system may be useful to blunt CD4+ T cell dependent allograft rejection and reduce CD8+ memory-induced transplant tolerance by modulating IL-15 responses