CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ helper T (Th) cells play a critical role in protective immune responses to
tumor cells. Particularly, Th9 cells exert anti-
tumor activity by producing
IL-9.
TNF receptor (TNFR)-associated factor 6 (
TRAF6) is an adaptor
protein that mediates the signals from both the TNFR superfamily and
Toll-like receptors (TLRs). We have previously reported that T cell-specific TRAF6-deficent (TRAF6ΔT) mice spontaneously developed systemic inflammatory diseases. However, the physiological role of
TRAF6 in T cells in controlling anti-
tumor immune responses remains largely unclear. Here, we found that
tumor formation of syngeneic
colon cancer cells inoculated in TRAF6ΔT mice was accelerated compared to that in control mice. Although TRAF6-deficient naïve T cells showed enhanced differentiation of Th9 cells in vitro, these T cells produced lower amounts of
IL-9 in response to a specific
antigen. Moreover, CD4+ tumor-infiltrating lymphocytes (TILs) in
tumor-bearing TRAF6ΔT mice expressed lower levels of
IL-9 than those in WT mice. Importantly, administration of recombinant
IL-9 (rIL-9) strongly suppressed
tumor progression in TRAF6ΔT mice. Furthermore, expression levels of the T-box
transcription factor Eomesodermin (Eomes) and its target molecules IFN-γ,
granzyme B and
perforin, as well as cytotoxic activity, were reduced in TRAF6-deficient CD8+ T cells in vitro. TRAF6-deficient T cells were found to express significantly increased levels of
immune checkpoint molecules, CTLA-4 and PD-1 on the cell surface. These results demonstrate that the
TRAF6 signaling pathway in T cells regulates anti-
tumor immunity through the activation of
tumor specific Th9 cells and CTLs in a tumor microenvironment.