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

J Immunol. 2001 Jan 1;166(1):103-11. doi: 10.4049/jimmunol.166.1.103.

Abstract

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 (alpha(4)beta(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-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Neoplasm
  • Binding Sites, Antibody
  • Binding, Competitive / immunology
  • CD4 Antigens / biosynthesis
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Cell Lineage / immunology
  • Cell Migration Inhibition
  • Cell Polarity / immunology
  • Chemokine CCL17
  • Chemokine CCL22
  • Chemokines, CC / antagonists & inhibitors
  • Chemokines, CC / blood
  • Chemokines, CC / metabolism*
  • Child
  • Cytokines / biosynthesis
  • Humans
  • Immunologic Memory*
  • Infant, Newborn
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Lymphocyte Activation
  • Membrane Glycoproteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CCR4
  • Receptors, CCR5 / biosynthesis
  • Receptors, CXCR3
  • Receptors, Chemokine / biosynthesis*
  • Receptors, Chemokine / blood
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • Th1 Cells / cytology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Th2 Cells / cytology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Neoplasm
  • CCL17 protein, human
  • CCL22 protein, human
  • CCR4 protein, human
  • CD4 Antigens
  • CTAGE1 protein, human
  • CXCR3 protein, human
  • Ccl17 protein, mouse
  • Ccl22 protein, mouse
  • Ccr4 protein, mouse
  • Chemokine CCL17
  • Chemokine CCL22
  • Chemokines, CC
  • Cxcr3 protein, mouse
  • Cytokines
  • Membrane Glycoproteins
  • Receptors, CCR4
  • Receptors, CCR5
  • Receptors, CXCR3
  • Receptors, Chemokine