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 (CD4Cre 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.