C-C chemokine receptor 4 expression defines a major subset of circulating nonintestinal memory T cells of both Th1 and Th2 potential

CCR4, a chemokine receptor for macrophage-derived chemokine (MDC) and thymu s and activation-regulated chemokine (TARC), has been implicated as a prefe rential marker for Th2 lymphocytes. Following in vitro polarization protoco ls, most Th2 lymphocytes express CCR4 and respond to its ligands TARC and M DC, whereas Th1 lymphocytes express CXC chemokine receptor 3 and CCR5 (but not CCR4). We show in this study that CCR4 is a major receptor for MDC and TARC on T lymphocytes, as anti-CCR4 mAbs significantly inhibit the migratio n of these cells to MDC and TARC, CCR4 is also highly expressed in most sin gle-positive CD4(+) thymocytes and on a major fraction of blood nonintestin al (alpha (4)beta (-)(7)) memory CD4 lymphocytes, including almost all skin memory CD4(+) cells expressing the cutaneous lymphocyte Ag (CLA), but weak ly or not expressed in other subsets in thymus and blood. interestingly, ma jor fractions of circulating CCR4(+) memory CD4 lymphocytes coexpress the T h1-associated receptors CXC chemokine receptor 3 and CCR5, suggesting a pot ential problem in using these markers for Th1 vs Th2 lymphocyte cells. More over, although production of Th2 cytokines in blood T cells is associated w ith CCR4(+) CD4 lymphocytes, significant numbers of freshly isolated circul ating CCR4(+) memory CD4 lymphocytes (including both CLA(+) and CLA(-) frac tions) readily express the Th1 cytokine IFN-gamma after short-term stimulat ion. Our results are consistent with a role for CCR4 as a major trafficking receptor for systemic memory T cells, and indicate that the patterns and r egulation of chemokine receptor expression in vivo are more complex than in dicated by current in vitro models of Th1 vs Th2 cell generation.