A role for CCR4 in development of mature circulating cutaneous T helper memory cell populations

Expression of the chemokine receptor CCR4 is strongly associated with trafficking of specialized cutaneous memory T helper (Th) lymphocytes to the skin. However, it is unknown whether CCR4 itself participates in the development of cutaneous Th populations. We have addressed this issue via competitive bone marrow ( BM) reconstitution assays; equal numbers of BM cells from CCR4(+/+) and CCR4(-/-) donors were allowed to develop side-by-side within RAG-1(-/-) hosts. Cells from both donor types developed equally well into B cells, naive CD8 T cells, naive CD4 T cells, interferon-gamma(+) Th1 cells, and interleukin-4(+) Th2 cells. In marked contrast, circulating cutaneous memory Th cells (i. e., E-selectin ligand(+) [E-lig(+)]) were more than fourfold more likely to be derived from CCR4(+/+) donors than from CCR4(+/+) donors. Most of this effect resides within the CD103(+) subset of the E-lig(+) Th population, in which donor CCR4(+/+) cells can outnumber CCR4(-/-) cells by > 12-fold. No similar effect was observed for alpha 4 beta 7(+) intestinal memory Th cells or CD103(+)/E-lig(-) Th cells. We conclude that CCR4 expression provides a competitive advantage to cutaneous Th cells, either by participating in their development from naive Th cells, or by preferentially maintaining them within the memory population over time.