CCL3 and CCL4 secretion by T regulatory cells attracts CD4+ and CD8+ T cells (P1077)

FOXP3+ T regulatory cells (Tregs) function to restrain immune responses. Accumulating evidence has shown that Tregs mediate their suppression by migrating to tissues based on their distinct expression of chemokine receptors. Yet how Tregs ensure they are close to their targets is unknown. Using ELISA and intracellular staining we discovered that both human and mouse Tregs produce CCL3 and CCL4, ligands for CCR5. Since chemokines recruit immune cells and the broad suppressive activities of Tregs require intimate cell proximity, we hypothesized that the secretion of the pro-inflammatory chemokines may bring immune cells closer to Tregs to be suppressed. To determine whether Tregs can recruit CD4+ and CD8+ cells via a CCR5-dependent mechanism, we performed migration assays and showed CCL3- and CCL4- containing-supernatants from Tregs attracted both subsets of T cells as well Tregs. Additionally, CCR5-/- T cells had a significantly reduced capacity to migrate towards Tregs in vitro and in vivo, supporting that chemokine signalling through CCR5 is critical. Furthermore, decreased proportion of FOXP3+CCL3+ Tregs was observed in patients with type 1 diabetes compared to healthy controls, implying that the altered chemokine secretion could contribute to the inadequate Treg function. These results suggest that active recruitment of their targets of suppression may be a novel mechanism of action by Tregs and that this pathway could be a potential therapeutic target in autoimmunity.