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

Abstract

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, antigendraining 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.

Functionally diverse human T cells recognize non-microbial antigens presented by MR1

“…To further support these findings, we next investigated the expression of three selected chemokine receptors known to be differentially expressed by T cell subsets with distinct functions (Becattini et al, 2015) and whose alternative combined expression regulates T cell recirculation and migration to diverse homing sites (Al-Banna et al, 2014; Bromley et al, 2008; Thomas et al, 2007). Both resting MR1T and MAIT cell clones displayed high levels of CXCR3 (with the exception of the DGA4 clone only; Figure 7B), However, we observed divergent expression patterns of CCR4 and CCR6 (Figure 7B), which further suggested that MR1T cells are heterogeneous and different from MAIT cells.…”

Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis

“…Given these reports, we cannot rule out that defective CXCL10 signaling in those cells including neutrophil and fibroblast-like synoviocytes might contribute to the inhibitory results of arthritis progression seen in Cxcl10 –/– and Cxcr3 –/– mice in our study. Furthermore, it has been reported that the accumulation of T cells in inflamed lymph nodes is highly CXCR3 dependent, but not CCR4 dependent [37]. Thus, we speculated that decreased recruitment of T cells in other organs including inflamed lymph nodes, not only in the synovium, would be observed in Cxcl10 –/– and Cxcr3 –/– mice; however, this hypothesis remains to be elucidated.…”

“…CAIA is reported to be induced by infiltration of neutrophils and macrophages, which are the main effector cells in CAIA, into the inflamed joints [20, 21, 36]. Al-Banna et al [37] showed that the accumulation of T cells in inflamed lymph nodes is highly CXCR3 dependent and that CXCR3 deficiency reduces the development of arthritis in a CIA model. In addition, Mohan and Issekutz [17] showed that blockade of CXCR3 inhibits T-cell and neutrophil recruitment to inflamed joints and decreases the severity of adjuvant arthritis.…”

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

“…It has been reported that the recruitment of Tregs is often associated with CCR4 and CCR5 chemokine receptors. CCR4 can mediate migration of Tregs to airway and to inflammation in skin, arthritic joints, and lymph nodes (34). CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart-mediating recruitment of Tregs (35).…”