TRAF3 as a regulator of T lymphocyte activation

T cells are an essential component of the adaptive immune system, which evolved to facilitate development of long-term, effective protection against infectious diseases. Upon activation, T cells play an important role in clearing infections, and especially, in preventing establishment of subsequent infections with the same pathogen. Because this is such a powerful response, it must be tightly regulated. Our lab has long been interested in how signaling molecules regulate the function of T and B lymphocytes. Our prior studies stimulated an interest in the signaling adapter molecule, Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3). Our group previously produced a T cell-conditional (CD4-Cre) TRAF3-/- mouse, which demonstrated that TRAF3 unexpectedly plays an important positive role in T cell functions, including providing help for B cell responses, protection from infectious pathogens, cytokine production and proliferation. After TCR engagement, TRAF3 associates with the T Cell Receptor (TCR)/CD28 complex. These data identified a new role for TRAF3 in T cell activation. There are three signals that are required for full T cell activation. The three types of receptors that deliver these signals are the TCR, co-stimulatory receptors and cytokine receptors. This dissertation explores the regulatory role of TRAF3 in the 3 signals required for T cellsactivation. In signal 1, TRAF3 enhances TCR signaling by regulating the localization of the TCR inhibitors, PTPase non-receptor type 22 (PTPN22) and the c-Src kinase (Csk). Our lab previously reported that recruitment of TRAF3 to the TCR complex requires co-stimulation of CD28, the primary receptor for signal 2. In this dissertation, we show that TRAF3 associates with the Linker of Activated T cells (LAT) complex, demonstrating preference for distinct LAT-associated proteins. For delivery of signal 3, T cells require stimulation of a cytokine receptor, such as IFNαR, for differentiation of a T cell to an effector cell. Upon IFN stimulation, TRAF3 inhibits IFNαR-induced early molecular events, which results in the regulation of both canonical and non-canonical IFNαR signaling pathways. The results presented in this dissertation highlight the dynamic roles of TRAF3 as a regulator of T cell activation, by regulating multiple T cell signaling pathways.