Chemokine receptor expression and function in CD4(+) T lymphocytes with regulatory activity

We have investigated the chemokine receptor expression and migratory behavi or of a new subset of nickel-specific skin-homing regulatory CD4(+) T cells (ThIL-10) releasing high levels of IL-10, low IFN-gamma, and undetectable IL-4. These cells inhibit in a IL-10-dependent manner the capacity of dendr itic cells to activate nickel-specific Tc1 and Th1 lymphocytes. RNase prote ction assay and FACS analysis revealed the expression of a vast repertoire of chemokine receptors on resting ThIL-10, including the Th1-associated CXC R3 and CCR5, and the Th2-associated CCR3, CCR4 and CCR8, the latter at high er levels compared with Th2 cells. The most active chemokines for resting T hIL-10, in terms of calcium mobilization and in vitro migration, were in or der of potency: CCL2 (monocyte chemoattractant protein-1, CCR2 ligand), CCL 4 (macrophage-inflammatory protein-1 beta, CCR5 ligand), CCL3 (macrophage-i nflammatory protein-1 alpha, CCR1/5 ligand), CCL17 (thymus and activation-r egulated chemokine, CCR4 ligand), CCL1 (I-309, CCR8 ligand), CXCL12 (stroma l-derived factor-1, CXCR4), and CCL11 (eotaxin, CCR3 ligand). Consistent wi th receptor expression down-regulation, activated ThIL-10 exhibited a reduc ed or absent response to most chemokines, but retained a significant migrat ory capacity to I-309, monocyte chemoattractant protein-1, and thymus and a ctivation-regulated chemokine. I-309, which was ineffective on Th1 lymphocy tes, attracted more efficiently ThIL-10 than Th2 cells. I-309 and CCR8 mRNA s were not detected in unaffected skin and were up-regulated at the skin si te of nickel-allergic reaction, with an earlier expression kinetics compare d with IL-10 and IL-4. Results indicate that skin-homing regulatory ThIL-10 lymphocytes coexpress functional Th1- and Th2-associated chemokine recepto rs, and that CCR8/I-309-driven recruitment of both resting and activated Th IL-10 cells may be critically involved in the regulation of Th1-mediated sk in allergic disorders.