Differing contributions of CCR4, E-selectin and VLA-4 to the migration of CD4 memory and activated CD4+CD25+ T cells to dermal inflammation. (95.2)

Abstract

CCR4 is on T cells in dermal inflammation and may mediate homing to skin. Our objective was to determine the expression and interaction of CCR4, E-selectin ligand (ESL) and a4β1 on memory and activated T cells in recruitment to dermal inflammation. A mAb to CCR4 (CR4.1) was developed. CCR4 was on ~10% of memory CD4 cells and 15% of these were ESL+. CCR4 and ESL were markedly increased on activated T cells. CCR4+ memory CD4 cells (memCCR4+) migrated 8-10 fold more to inflammation induced by cytokines, TLR agonists and DTH, than memCCR4- cells, and homed less to LNs. CCR4+ anti-TCR activated CD4 cells (actCCR4+) migrated only 50% better to skin than actCCR4- cells. E-selectin blockade inhibited 50-75% of actCCR4+, but not memCCR4 cell migration. a4β1 blockade had an inverse effect, i.e. inhibiting memCCR4+ more than actCCR4+ cells, while P-selectin blockade had no effect. Thus, CCR4 is on a subset of memCD4 cells with dermal tropism, but this selective homing is reduced on activated CD4+CD25+cells. The role of ESL and a4β1 also differs between activated and memory CCR4+ cells, with a decrease in the role of ESL and an increase in a4β1 with differentiation to long-term memory. (Supported by the CIHR).