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*
Millennium Pharmaceuticals, Cambridge, MA 02139; and
Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
CCR4, a chemokine receptor for macrophage-derived chemokine (MDC)
and thymus and activation-regulated chemokine (TARC), has been
implicated as a preferential marker for Th2 lymphocytes. Following in
vitro polarization protocols, most Th2 lymphocytes express CCR4 and
respond to its ligands TARC and MDC, 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 migration of these cells
to MDC and TARC. CCR4 is also highly expressed in most single-positive
CD4+ thymocytes and on a major fraction of blood
nonintestinal (
4
7-) memory
CD4 lymphocytes, including almost all skin memory CD4+
cells expressing the cutaneous lymphocyte Ag (CLA), but weakly or not
expressed in other subsets in thymus and blood. Interestingly, major
fractions of circulating CCR4+ memory CD4 lymphocytes
coexpress the Th1-associated receptors CXC chemokine receptor 3 and
CCR5, suggesting a potential problem in using these markers for Th1 vs
Th2 lymphocyte cells. Moreover, although production of Th2 cytokines in
blood T cells is associated with CCR4+ CD4 lymphocytes,
significant numbers of freshly isolated circulating CCR4+
memory CD4 lymphocytes (including both CLA+ and
CLA- fractions) readily express the Th1 cytokine IFN-
after short-term stimulation. 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 regulation of chemokine receptor
expression in vivo are more complex than indicated by current in vitro
models of Th1 vs Th2 cell generation.
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