TRAF3 Regulates Homeostasis of CD8+ Central Memory T Cells

Our laboratory reported previously that TNF receptor associated factor 3 (TRAF3) is a positive regulator of TCR signaling and T cell function. In the current study, we present new findings that reveal differential roles for TRAF3 in the regulation of CD4 + and CD8 + T cells. In response to TCR stimulation in vitro , TRAF3 has greater impact in CD4 + T cells than in CD8 + T cells. However, T cell-specific TRAF3 deficient mice (CD4 Cre TRAF3 fl ° x/fl ° x ; T-TRAF3 −/− ) have a greater number of CD4 + CD44 hi effector/memory T cells than littermate control (LMC) mice, possibly due to an inefficient suppressive effect of TRAF3 deficient Foxp3 + regulatory T cells. In contrast, CD8 + CD44 hi CD62L hi central memory (Tcm) cells are markedly reduced in T-TRAF3 −/− mice in comparison to LMC mice, although CD8 + CD44 hi CD62L l ° w effector memory T (Tem) cells and naïve T cells (CD8 + CD44 l ° w CD62L hi ) do not show significant differences in number. Importantly, TRAF3-deficient Tcm cells exhibit defective homeostasis due to impaired IL-15 signaling. These results indicate that the involvement of TRAF3 in IL-15 mediated signaling to T cells plays a previously unappreciated and critical role in CD8 + Tcm cell regulation and maintenance.