TRAF3 as a regulator of T lymphocyte activation

Abstract

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 cellconditional (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 vii signal 3, T cells require stimulation of a cytokine receptor, such as IFNR, for differentiation of a T cell to an effector cell. Upon IFN stimulation, TRAF3 inhibits IFNR-induced early molecular events, which results in the regulation of both canonical and non-canonical IFNR 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.

TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization

“…Because TRAF3 regulates PTPN22 in both B and T cells, we first examined if TRAF3 inhibits IFNαR signaling via PTPN22. Stimulation of PTPN22‐deficient HuT28.11 cells with type 1 IFN recapitulates the phenotype seen in TRAF3‐deficient T cells . STAT1 is a known target for PTPN22, and association between PTPN22 and JAK1 results in JAK1 dephosphorylation, inhibiting downstream signaling .…”

“…T cell proliferation and the activation of extracellular signal‐regulated kinase (Erk), a member of the noncanonical MAPK pathway in the IFNαR‐signaling pathway, also increase with IFN stimulation in the absence of TRAF3. Interestingly, IFN‐induced proliferation and Erk activation in PTPN22‐deficient T cells are not detectably different from the response of the HuT28.11 parent cell line, in contrast to the phenotype of the TRAF3‐deficient Hut28.11 cells . These data suggest that the regulatory role of TRAF3 in IFN‐stimulated MAPK signaling is not completely dependent upon the recruitment of PTPN22, implicating the potential involvement of other phosphatases that inhibit IFNαR signaling.…”

“…Similar to the inhibitory roles of TRAF3 in B cell IL‐6R and T cell IL‐2R signaling, the loss of TRAF3 in primary T cells increases canonical IFN‐induced STAT1 phosphorylation at both Y701 and S727 sites . Interestingly, a unique feature of TRAF3's regulation of IFNαR signaling is that increases in phosphorylation of STAT1 correlate with increases in total STAT1 protein levels, a feature not observed in TRAF3‐mediated regulation of IL‐6R or IL‐2R signaling.…”

“…TCPTP also regulates the phosphorylation of STAT1 induced by IFN‐γ stimulation in CD4 + T con cells . In the absence of TRAF3, IFN stimulation also increases the phosphorylation of STAT1, so it will be of interest to determine whether TRAF3 also recruits TCPTP to IFN receptors. Together, these data identified a new inhibitory role for TRAF3 in IL‐2R signaling, which is mediated by recruiting TCPTP to the IL‐2R complex, where TCPTP dephosphorylates JAK1 and JAK3 to inhibit the downstream IL‐2R signaling pathway.…”

“…Our lab recently identified a role for TRAF3 in regulating PD‐1 through the IFNαR signaling pathway. In the absence of TRAF3, naive CD4 + and CD8 + T cells display a 4‐fold increase in membrane expression of PD‐1 . IFNαR signaling is a key pathway known to upregulate PD‐1 expression .…”