Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells

Chemokines dictate regional trafficking of functionally distinct T cell sub sets. In rodents and humans, a unique subset of CD4(+)CD25(+) cytotoxic T l ymphocyte antigen (CTLA)-4(+) regulatory T cells (Treg) has been proposed t o control peripheral tolerance. However, the molecular basis of immune supp ression and the trafficking properties of Treg cells are still unknown. Her e, we determined the chemotactic response profile and chemokine receptor ex pression of human blood-borne CD4(+)CD25(+) Treg cells. These Treg cells we re found to vigorously respond to several inflammatory and lymphoid chemoki nes. Treg cells specifically express the chemokine receptors CCR4 and CCR8 and represent a major subset of circulating CD4(+) T cells responding to th e chemokines macrophage-derived chemokine (MDC)/CCL22, thymus and activatio n-regulated chemokine (TARC)/CCL17, I-309/CCL1, and to the virokine vMIP-1 (ligands of CCR4 and CCR8). Blood-borne CD4(+) T cells that migrate in resp onse to CCL1 and CCL22 exhibit a reduced alloproliferative response, depend ent on the increased frequency of Treg cells in the migrated population. Im portantly, mature dendritic cells preferentially attract Treg cells among c irculating CD4(+) T cells, by secretion of CCR4 ligands CCL17 and CCL22. Ov erall, these results suggest that CCR4 and/or CCR8 may guide Treg cells to sites of antigen presentation in secondary lymphoid tissues and inflamed ar eas to attenuate T cell activation.