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 TRAF3fl°x/fl°x; T-TRAF3-/-) have a greater number of CD4+CD44hi 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+CD44hiCD62Lhi central memory (Tcm) cells are markedly reduced in T-TRAF3-/- mice in comparison to LMC mice, although CD8+CD44hiCD62Ll°w effector memory T (Tem) cells and naïve T cells (CD8+CD44l°wCD62Lhi) 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.
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