CCR5-dependent homing of naturally occurring CD4⁺ regulatory T cells to sites of Leishmania major infection favors pathogen persistence

Pathogen persistence after clinical cure is a hallmark of many chronic infections. Previously, we showed that naturally occurring CD4⁺CD25⁺ regulatory T (nTreg) cells rapidly accumulate within chronic dermal sites of Leishmania major infection where they suppress anti-pathogen CD4⁺ T cell responses, favor parasite persistence and dermal pathology, and consequently control concomitant immunity. Here, we postulated that chemokines might direct nTreg cell homing in sites of infection and show that CD4⁺CD25⁺ nTreg cells, compared with normal CD4⁺ T cells, preferentially express the CCR5 chemokine receptor, which enables them to migrate in response to CCR5 ligands in vitro. We show that in contrast to their wild-type (WT) counterparts, CCR5^−/− CD4⁺CD25⁺ nTreg cells resulted in an increased magnitude of parasite-specific, interferon γ–producing CD4⁺ T cells within infection sites, dramatically reduced parasite numbers, and potent resistance to infection, a finding consistent with the clinical outcome of infected CCR5^−/− mice. Interestingly, this resistance was related to an inefficient migration of CCR5^−/− nTreg cells to infected dermal sites compared with WT nTreg cells. Thus, this study shows that CCR5 directs the homing of CD4⁺CD25⁺ nTreg cells to L. major–infected dermal sites where they promote the establishment of infection and long-term survival of the parasite in the immune host.