Expression of the Chemokine Receptors CCR4, CCR5, and CXCR3 by Human Tissue-Infiltrating Lymphocytes

Abstract

Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4 ؉ lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4؉ populations in blood, as well as by tissueinfiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4؉ lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69 ؉ ). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in ␣ 4 ␤ 7 expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation.

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

“…Previous studies have shown that CXCR3 is expressed, together with several other CKR, on T cells in inflamed tissues [1][2][3][4][5][6], and in dermal inflammation the T cell expression of the skin-homing CKR CCR4 and CCR10 has been the subject of focus [12][13][14][15][16]. In addition, CCR2, CCR5 and CXCR6 are also present on infiltrated T cells [4,5].…”

“…Thus, although the CXCR3 + subset is a minority (*15%) of T cells within the memory T cell subpopulation, it includes most of the T cells recruited to dermal inflammation. This may be because of the importance of CXCR3 in this migration, or because CXCR3 + T cells co- express other CKR, such as CCR2, CCR4 and CCR5, which contribute to T cell infiltration [13]. Indeed, rat memory CD4 T cells are *15% CCR2 + , 10-15% CCR4 + , *2% CXCR6 + and have low levels of CCR5 message, while CD8 T cells are *9% CCR2 + and *3% CXCR6 + , and have low levels of CCR4 and CCR5 (unpublished observations).…”

“…In contact sensitivity and in psoriasis, many of the infiltrating T lymphocytes in the skin express abundant CCR4 and CCR10 [12][13][14][15][16]. These CCR4 + cells also express the cutaneous lymphocyte antigen (CLA), a ligand for E-selectin [12,17,18].…”

Differing Requirements for CCR4, E-Selectin, and α4β1 for the Migration of Memory CD4 and Activated T Cells to Dermal Inflammation

“…It is also detected on T cells in psoriatic lesions and induced blisters (10,11). The production of CCR4 ligands in atopic dermatitis lesions (7) is thought to attract CCR4 + CD4 T cells (12), but the relationship between CCR4 and the migration of multiple CCR4 + T cell subsets is unknown.…”

“…Other CKRs also contribute to skin homing of T cells. Ligands of CXCR3 and CCR10 are produced in inflamed skin, and both CXCR3 and CCR10 are expressed on skin-infiltrating T cells in humans (11,13). Blockade of CXCR3 was shown to inhibit 90% of the migration of T cell lymphoblasts to dermal inflammation (14), even though CCR4 is coexpressed on about half of the CXCR3 + CD4 T cells (6).…”