The Indispensable Role of CCR5 for In Vivo

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 2 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 2 Tregs and accumulated more in tumors than did CD103 2 Tregs. Furthermore, blockade of CCR5 signaling, either by CCR5 2/2 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. R egulatory T cells (Tregs) play an important role in the maintenance of immunological tolerance and in control of excessive immune responses against self-antigens (1, 2). Recently, Tregs have been shown to be phenotypically and functionally heterogeneous and composed of effector/memory Tregs and naive Tregs (3–7). CD103 is a cell surface protein of the integrin family and is proposed as a marker for effector/memory Tregs in mice (3–6). These CD103 + Tregs are more potent in suppressing harmful inflammatory reactions compared with CD103 2 Tregs in different mouse models of autoimmune diseases and Leishmania infection (3, 4, 6). In contrast, we also reported that CD103 + Tregs were potent suppressors of anti-tumor immune responses in tumor-bearing mice (8). Recent studies have also shown that CD103 is a hallmark of tumor-infiltrating Tregs in TGF-b– secreting tumor (9). However, the mechanisms underlying the control of immune responses by CD103 + Tregs remain unclear. It has been reported that a preferential migration of Tregs into inflamed tissue may be driven by differences in homing signaling in models of infection/inflammation and malignancy (10–12). The high expression levels of chemokine receptors have been demonstrated to promote such preferential migration of Tregs into tissue sites of disease (10–12). Recent …