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(flox/flox); 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, CD(8+)CD44(hi)CD62L(hi) central memory (Tcm) cells are markedly reduced in T-TRAF3(-/-) mice in comparison to LMC mice, although CD(8+)CD44(hi)CD62L(low) effector memory T (Tem) cells and naive T cells (CD(8+)CD44(low) 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 CD(8+)Tcm cell regulation and maintenance.