The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Abstract

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.

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

“…19,20 Here, we further explored this notion and focused on these effector Treg cells. The effector Treg cells, defined as CD103 C Treg cells, as the tumor-associated Treg cells in murine tumor model had also been proposed in our lab 4,5 and others. 29 CD45RA ¡ Foxp3 high Treg cell was proposed as human counterpart of effector Treg cell by Miyara and colleagues recently.…”

“…Recently, we have shown effector Treg cells with higher CD103 expression were increased in CT26 tumor-bearing mice and were responsible for inhibiting CD8 C T cell-mediated antitumor immune responses. 4,5 We therefore investigated the phenotypes of these Treg cells in these animal models. The frequencies of splenic …”

“…19 Similar observations had been described as well. 5,20,21 It is not presently clear whether TNF-a/TNFR2 pathway could enhance the migration of Treg cells into the tumor microenvironment through chemokine/chemokine receptor interactions. Our recent study showed that effector Treg cells had more potent in vivo suppressive ability in inhibiting CD8 C T cell-mediated antitumor immune response.…”

“…This potent in vivo suppression ability of effector Treg cells is not due to the stronger suppression ability per cell but possibly due to the tissue-migration ability through CCR5 expression. 5 Thus, it is possible that TNF-a enhances in vivo suppressive function of effector Treg cells through increasing their tissue-migration ability. Further study is warranted to elucidate this possibility.…”

“…4,5 In human studies, Sakaguchi's group demonstrated CD45RA ¡ Foxp3 high Treg cells as effector Treg cells which are increased in patients with cancer. 1,6 We have also shown these CD45RA ¡ Foxp3 high effector Treg cells were highly suppressive, accumulated in tumor tissues and correlated with disease progression in patients with CRC.…”