Differing Requirements for CCR4, E-Selectin, and α4β1 for the Migration of Memory CD4 and Activated T Cells to Dermal Inflammation

Abstract

CCR4 on T cells is suggested to mediate skin homing in mice. Our objective was to determine the interaction of CCR4, E-selectin ligand (ESL), and α4β1 on memory and activated T cells in recruitment to dermal inflammation. mAbs to rat CCR4 were developed. CCR4 was on 5–21% of memory CD4 cells, and 20% were also ESL+. Anti–TCR-activated CD4 and CD8 cells were 40–55% CCR4+, and ∼75% of both CCR4+ and CCR4− cells were ESL+. CCR4+ memory CD4 cells migrated 4- to 7-fold more to dermal inflammation induced by IFN-γ, TNF, TLR agonists, and delayed-type hypersensitivity than CCR4− cells. CCR4+ activated CD4 cells migrated only 5–50% more than CCR4− cells to these sites. E-selectin blockade inhibited ∼60% of CCR4+ activated CD4 cell migration but was less effective on memory cells where α4β1 was more important. Anti-α4β1 also inhibited CCR4− activated CD4 cells more than CCR4+ cells. Anti–E-selectin reduced activated CD8 more than CD4 cell migration. These findings modify our understanding of CCR4, ESL, α4β1, and dermal tropism. There is no strict relationship between CCR4 and ESL for skin homing of CD4 cells, because the activation state and inflammatory stimulus are critical determinants. Dermal homing memory CD4 cells express CCR4 and depend more on α4β1 than ESL. Activated CD4 cells do not require CCR4, but CCR4+ cells are more dependent on ESL than on α4β1, and CCR4− cells preferentially use α4β1. The differentiation from activated to memory CD4 cells increases the dependence on CCR4 for skin homing and decreases the requirement for ESL.

CCR4+ Skin-Tropic Phenotype as a Feature of Central Memory CD8+ T Cells in Healthy Subjects and Psoriasis Patients

“…Its role could however change under inflammatory conditions, where other chemokines could play a major role in the recruitment of effector memory/effector T cells (27,33). Consistent with this view, different groups evidenced that T cell mediated skin-inflammation is largely independent of CCR4 and rather requires CXCR3 (34,35).…”

Neutrophil trails guide influenza-specific CD8 + T cells in the airways

“…S4 and ref. (26, 27)). Two known neutrophil chemokines, CXCL1 and CXCL2, were excluded from the analysis due to the lack of receptor expression on CD8 + T cells (fig.…”

CD4 T-Cell Memory Generation and Maintenance

“…CD62L and CCR7 are absent or poorly expressed by Tem while alternative adhesion molecules that facilitated entry into nonlymphoid target tissues are up-regulated. 141–143 Tem express lineage-specific transcriptional programs and produce appropriate cytokines upon rechallenge, but tend to lack the full proliferative potential of Tcm.…”