CCR4 versus CCR10 in human cutaneous TH lymphocyte trafficking

Abstract

The chemokine receptors (CCRs) CCR4 and CCR10, and the cutaneous lymphocyte antigen (CLA), have each been proposed as critical mediators of skin-specific T H lymphocyte homing in mice and humans. CLA initiates skin homing by mediating E-selectin-dependent tethering and rolling within cutaneous venules, but the specific roles of CCR4 and CCR10 are unclear. We have generated an antihuman CCR10 monoclonal antibody (mAb; 1B5) to illuminate the individual contributions of these molecules. This mAb allows us to compare CCR10, CCR4, and CLA expression within human T H populations. The mAb 1B5 recognizes functional CCR10 expression, as chemotactic responsiveness to cutaneous T-cell-attracting chemokine (CTACK)/CCL27 (a CCR10 ligand) parallels the staining of T H subsets. We find CCR10 expressed by only a minority (approximately 30%) of bloodborne, skin-homing (CLA ؉ /CCR4 ؉ ) T H cells. However, essentially all members of the relatively small "effector" (CLA ؉ / CCR4 ؉ /CD27 ؊ /CCR7 ؊ ) skin-homing T H population express CCR10. Most skininfiltrating lymphocytes in allergic delayed-type hypersensitivity (DTH) and bacterial chancroid skin lesions express both CCR4 and CLA, but only about 10% express CCR10. This suggests for the 2 models of T H skin homing studied here that CCR10 ؉ T H cells have no advantage over other CLA ؉ /CCR4 ؉ T H cells in homing to cutaneous sites. We conclude that the skin-homing T H compartment is itself divided into distinct subpopulations, the smaller of which expresses both CCR4 and CCR10, and the larger of which expresses only CCR4. Thus, CCR10 is unlikely to be necessary for cutaneous homing of T H cells in the models studied here. CCR10 may instead play a role in the movement of specialized "effector" cutaneous T H cells to and/or within epidermal

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

“…Current evidence suggests that during immunologic priming, the site and, in particular, the specific draining LN imprint the ensuing immune response with lasting tissue-selective tropism. This is, in part, accomplished by the acquisition of differential homing instructions, including, but not limited to, unique adhesion molecules (30 -32) and chemoattractant receptors (25)(26)(27)(28)(29) that direct lymphocytes to tissues in which they are most likely to re-encounter their cognate Ag. Indeed, memory/effector T cells have been identified that selectively home to cutaneous (45)(46)(47) and various mucosal (30,31,33) tissues.…”

“…Current evidence suggests that upon stimulation in local draining LNs), naive T cells are imprinted with a unique repertoire of chemoattractant receptors (25)(26)(27)(28)(29) and adhesion molecules (30 -32) that privilege them to survey tissues most likely to contain their cognate Ag. Indeed, recent observations have established that the local LN microenvironment and the tissue origin of Ag-bearing dendritic cells are major determinants in the programming for tissue-selective homing properties (33)(34)(35)(36).…”

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

“…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]. CCR10 binding to CCL27 can also mediate T cell migration to dermal inflammation.…”

Cutting Edge: Chemokine Receptor CCR4 Is Necessary for Antigen-Driven Cutaneous Accumulation of CD4 T Cells under Physiological Conditions

“…First is the discovery that a second chemokine receptor, CCR10, is associated with cutaneous T cells (3,4). This discovery raised the possibility that CCR10 might be redundant with, or more important than CCR4 in skin-specific trafficking.…”