CONTRIBUTION OF CCR4 AND CXCR3 IN THE MIGRATION OF T CELLS TO INFLAMMATORY SITES IN THE SKIN, JOINTS AND LYMPH NODES

Abstract

Chemokine receptors, CCR4 and CXCR3, found on T cells, are implicated in the inflammatory response in the skin, joint and lymph nodes (LNs), but whether they mediate T cell recruitment is unclear. Therefore, I examined the contribution of CCR4 and CXCR3 in T cell recruitment to inflammatory sites in the skin, joints and LNs. I found that CXCR3 deficiency reduced the migration of ~50% of the CD4 cells, ~60% of Th1 cells and ~30% of Tc1 cells to inflamed skin. However, the dermal recruitment of memory CD4 and Th1 cells was associated with CCR4 expression, but did not require CCR4. Surprisingly, CCR4 deficiency increased the recruitment of memory CD4 cells and Treg cells to some inflamed skin sites, and reduced the infiltration of Th2 and Tc2 cells to ConA by ~30%, but did not affect TLR agonist sites. Differing contributions of CXCR3 and CCR4 in the Th1 cell homing to LNs draining sites of CFA-immunization was demonstrated; the accumulation of CXCR3-/- Th1 cells was reduced, while the accumulation of CCR4-/- Th1 cells was increased. However, the deficiency of both CCR4 and CXCR3 did not affect recruitment of Th1 cells to inflamed paws of mice with collagen induced arthritis (CIA). Interestingly, CCR4-/- mice developed CIA with reduced incidence. While CCR4-/- Th1 cells migrated normally to inflamed paws of wild-type mice, CCR4-/- mice had fewer CD4 CD25+ cells in the draining LNs and recruited fewer Th1 cells into the inflamed paws, suggesting a role for CCR4 on immune cells or stromal cells. In summary, the contribution of CXCR3 varies in different tissues; it mediates part of Th1 cell recruitment to dermal inflammation and draining LNs, but not joint inflammation. The contribution of CXCR3 and CCR4 to dermal recruitment differs with T cell subsets. While CXCR3 mediates memory CD4, Th1 and Tc1 cell recruitment, CCR4 mediates Th2 and Tc2 cell recruitment to ConA sites. CCR4 is associated with, but does not mediate, memory CD4 and Th1 cell migration. Instead, the increased accumulation of CCR4-/- T cells was observed; memory CD4 and Treg cells in ConA, and Th1 cells in draining LNs.