CCR4 and CXCR3 play different roles in the migration of T cells to inflammation in skin, arthritic joints, and lymph nodes.

CCR4 and CXCR3 are expressed on several T-cell subsets in inflamed tissues, yet their role in tissue-specific recruitment is unclear. We examined the contributions of CCR4 and CXCR3 to T-cell recruitment into inflamed joints in collagen-induced arthritis, antigen-draining lymph nodes (LNs) and dermal inflammatory sites (poly I:C, LPS, concanavalin A, and delayed type hypersensitivity), using labeled activated T cells from CXCR3(-/-), CCR4(-/-), and WT mice. Both CXCR3 and CCR4 deficiency reduced the development of arthritis, but did not affect Th1-cell recruitment to the inflamed joints. Accumulation in inflamed LNs was highly CXCR3 dependent. In contrast, CCR4-deficient Th1 cells had an increased accumulation in these LNs. Migration to all four dermal inflammatory sites by activated Th1 and T cytotoxic cells and memory CD4(+) T cells was partially CXCR3-dependent, but Treg-cell migration was independent of CXCR3. The subset of cells expressing CCR4 has skin-migrating properties, but CCR4 itself is not required for the migration. Thus, migration into these inflamed tissues is CCR4-independent, and partially dependent on CXCR3, except for Treg cells, which require neither receptor. CCR4 may therefore affect retention of T cells in different tissues rather than trafficking out of the blood.

Differing requirements for CCR4, E-selectin, and α4ß1 for the migration of memory CD4 and activated T cells to dermal inflammation.

CCR4 on T cells is suggested to mediate skin homing in mice. Our objective was to determine the interaction of CCR4, E-selectin ligand (ESL), and α(4)ß(1) on memory and activated T cells in recruitment to dermal inflammation. mAbs to rat CCR4 were developed. CCR4 was on 5-21% of memory CD4 cells, and 20% were also ESL(+). Anti-TCR-activated CD4 and CD8 cells were 40-55% CCR4(+), and ∼75% of both CCR4(+) and CCR4(-) cells were ESL(+). CCR4(+) memory CD4 cells migrated 4- to 7-fold more to dermal inflammation induced by IFN-γ, TNF, TLR agonists, and delayed-type hypersensitivity than CCR4(-) cells. CCR4(+) activated CD4 cells migrated only 5-50% more than CCR4(-) cells to these sites. E-selectin blockade inhibited ∼60% of CCR4(+) activated CD4 cell migration but was less effective on memory cells where α(4)ß(1) was more important. Anti-α(4)ß(1) also inhibited CCR4(-) activated CD4 cells more than CCR4(+) cells. Anti-E-selectin reduced activated CD8 more than CD4 cell migration. These findings modify our understanding of CCR4, ESL, α(4)ß(1), and dermal tropism. There is no strict relationship between CCR4 and ESL for skin homing of CD4 cells, because the activation state and inflammatory stimulus are critical determinants. Dermal homing memory CD4 cells express CCR4 and depend more on α(4)ß(1) than ESL. Activated CD4 cells do not require CCR4, but CCR4(+) cells are more dependent on ESL than on α(4)ß(1), and CCR4(-) cells preferentially use α(4)ß(1). The differentiation from activated to memory CD4 cells increases the dependence on CCR4 for skin homing and decreases the requirement for ESL.

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

Lymphocytes in inflamed tissues express numerous chemokine receptors. The relative importance of these receptors for migration in inflammation is unclear. The role of CXCR3 in T cell subset migration was examined using monoclonal antibodies developed to rat CXCR3. CXCR3 was expressed on sixfold more CD8(+) ( approximately 30%) than CD4(+) ( approximately 5%) T cells in spleen, lymph nodes and blood, and on approximately 10% of CD4(+)CD45RC(-) (memory) and approximately 50% of CD8(+)CD45RC(+) spleen T cells. After immunization, CXCR3 increased tenfold on CD4(+) lymph node lymphoblasts ( approximately 55%), and >90% of inflammatory exudate T cells were CXCR3(+). CXCR3(+) T cells migrated significantly better than CXCR3(-) T cells to all dermal inflammatory stimuli tested in vivo, even though these T cells are a minority of the memory T cells. Blocking CXCR3 inhibited recruitment of 60-85% of unstimulated T cells and up to 90% of CD8(+)CD45RC(+) effector T cells, but caused <50% inhibition of CD4(+) and CD8(+) memory (CD45RC(-)) T cells. About 90% of T lymphoblast migration to IFN-gamma, IFN-gamma plus TNF-alpha, polyinosinic polycytidylic acid, lipopolysaccharide, and delayed-type hypersensitivity (DTH)-induced inflammation was inhibited. Blockade also reduced DTH-induced induration. Thus, CXCR3 has a non-redundant role in T cell migration to dermal inflammation and is critical for activated T lymphoblast recruitment, but memory T cells are less dependent on CXCR3 for their infiltration.