CCR8⁺FOXp3⁺ T_reg cells as master drivers of immune regulation

The current study identifies CCR8⁺ regulatory T cells (T_reg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of T_reg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating T_reg cells. The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by T_reg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8⁺ regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in T_reg cells was further dissected through adoptive transfer studies using CCR8^-/- mice. Collectively, we demonstrate the pivotal role of CCR8⁺ T_reg cells in restraining immunity and highlight the potential clinical implications of this discovery.