C-C Chemokine Receptor 4 Expression Defines a Major Subset of Circulating Nonintestinal Memory T Cells of Both Th1 and Th2 Potential

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 (α4β7−) 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-γ 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.

CXCR3 is required for migration to dermal inflammation by normal andin vivo activated T cells: differential requirements by CD4 and CD8 memory subsets

“…This suggested that a 4 b 1 vascular cell adhesion molecule-1 binding was required for part of this migration, but that the accumulation was also mediated through E-selectin-CLA interactions. Since CLA is co-expressed with CCR4 on T cells [12,14,17], it is interesting to speculate that the a 4 b 1 -mediated migration is stimulated through an alternate CKR, likely CXCR3, on at least some T cell subsets. Indeed, blockade of a 4 b 1 has been most effective in inhibiting T cell migration to IFN-c, which would strongly induce CXCR3 ligands [26].…”

“…These CCR4 + cells also express the cutaneous lymphocyte antigen (CLA), a ligand for E-selectin [12,17,18]. This suggests that T cell homing to inflamed skin is governed by tissue-specific interactions mediated by CLA and CCR4 on T cells interacting with E-selectin and CCL17 on endothelium [19,20].…”

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

“…Immunological memory to cutaneous Ags (e.g., nickel, house dust mite) is mainly carried within this population compared with memory for systemic Ags (e.g., tetanus toxid) that is found in the much larger CLA Ϫ memory T cell population (5,32,(35)(36)(37). CLA ϩ T cells make Th1 (IFN-␥), Th2 (IL-4, IL-5), and other (IL-10) cytokines that may direct how the immune system will mount a response (25,27,32,35,(37)(38)(39)(40). Based on these attributes, CLA ϩ T cells are thought to contribute significantly to the host response to cutaneous encountered Ags.…”

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…A number of inflammatory molecules were among the ones whose up-regulation was inhibited by abatacept (CCL17, CCL22, CXCL16, CXCL9, and CD40). Many of these molecules are T cell chemoattractants and could potentially facilitate cellular interactions (31)(32)(33)(34). IPA predicted both inhibition of functions, Values are the mean 6 SEM of 5 mice per group.…”