The indispensable role of CCR5 for in vivo suppressor function of tumor-derived CD103⁺ effector/memory regulatory T cells

CD103 is a marker for identification of effector/memory regulatory T cells (Tregs). CD103⁺ Tregs are potent suppressors of tissue inflammation in several infectious diseases, autoimmune diseases, and cancers. However, the underlying mechanisms for this potent suppression ability remain unclear. The current study was designed to clarify this issue. Unexpectedly, we found both CD103⁺ and CD103^- Tregs had similar suppression capacity in vitro. We then chose a murine tumor model for investigation of the in vivo behavior of these Tregs. The suppression ability in vivo against the anti-tumor ability of CD8⁺ T cells was restricted to CD103⁺Tregs although both Tregs had equal in vitro suppression ability. In addition, CD103⁺ Tregs expressed significantly higher levels of CCR5 than those of CD103^- Tregs and accumulated more in tumors than did CD103 ^- Tregs. Furthermore, blockade of CCR5 signaling, either by CCR5 ^-/-CD103⁺ Tregs or by CCL5 knockdown tumor, could reduce the migration of CD103⁺ Tregs into tumors and impair their in vivo suppression ability. In conclusion, these results indicate that the potent in vivo suppression ability of CD103⁺ Tregs is due to the tissue-migration ability through CCR5 expression.