Pulmonary CCL18 Recruits Human Regulatory T Cells

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Abstract
CCL18 is both a constitutively expressed and an inducible chemokine, whose role in the inflammatory reaction is poorly known. The aim of this study was to evaluate whether CCL18 has the capacity to attract human T cells with a regulatory function (regulatory T cells [Treg]). Results from chemotaxis assays performed on different types of Treg showed that CD4+CD25+CD127low cells, but neither T regulatory type 1 clones nor Treg differentiated in vitro with anti-CD3/CD46 mAbs, were recruited by CCL18 in a dose-dependent manner. CCL18-recruited memory CD4+ T cells were enriched in CD25high, CD25+CD127low, latency-associated peptide/TGF-β1, and CCR4-expressing T cells, whereas there was no enrichment in Foxp3+ cells as compared with controls. Stimulated CCL18-recruited memory T cells produced significantly increased amounts of the regulatory cytokines IL-10 and TGF-β1, as well as IL-4, but not IFN-γ and IL-17. Cell surface CCL18 binding was found predominantly on IL-10+ (26.3 ± 5.8%) and on a few latency-associated peptide/TGF-β1+ (18.1 ± 1.9%) and IL-4+ (14.5 ± 2.9%) memory T cells. In an in vivo model of SCID mice grafted with human skin and reconstituted with autologous PBMCs, the intradermal injection of CCL18 led to the cutaneous recruitment of CD4+, CD25+, and IL-10+ cells, but not Foxp3+ cells. Furthermore, CCL18-recruited memory T cells inhibited the proliferation of CD4+CD25− effector T cells through an IL-10–dependent mechanism. These data suggest that CCL18 may contribute to maintaining tolerance and/or suppressing deleterious inflammation by attracting memory Tregs into tissues, particularly in the lung, where it is highly and constitutively expressed.

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