The chemokine CCL18 generates adaptive regulatory T cells from memory CD4+ T cells of healthy but not allergic subjects

The purpose of this study was to assess the direct effect of CCL18, a chemokine elevated in allergic diseases and induced by Th2 cytokines, on the polarization of human CD4(+) T cells. Purified human T cells from healthy subjects were pretreated or not with CCL18, and evaluated for cytokine production. CCL18-pretreated memory but not naive CD4(+) T cells exhibited an increased production of IL-10 (12.3 +/- 2.6 vs. 5.6 +/- 0.9 ng/ml for medium) and TGF-beta 1 but not IL-4, IFN-gamma, and IL-17 compared with control cells. Pretreatment of highly purified CD4(+) CD25(-) memory T cells with CCL18 led to their conversion to CD4(+) CD25(-) Foxp3(+) regulatory T cells able to inhibit the proliferation of CD4(+) CD25(-) effector T cells by both cytokine and cell contact-dependent mechanisms. However, this regulatory effect of CCL18 was lost when T cells originated from allergic subjects in relation with a decreased binding of CCL18 to these cells [0.7 +/- 0.3 mean fluorescence intensity (MFI)] as compared to those from healthy subjects (6.0 +/- 1.7 MFI). This study is the first to define a chemokine that generates adaptive regulatory T cells from CD4(+) CD25(-) memory T cells. This mechanism appears defective in allergic patients and may underlie the decreased tolerance observed in allergic diseases.-Chang, Y., de Nadai, P., Azzaoui, I., Morales, O., Delhem, N., Vorng, H., Tomavo, S., Ait Yahia, S., Zhang, G., Wallaert, B., Chenivesse, C., Tsicopoulos, A. The chemokine CCL18 generates adaptive regulatory Tcells from memory CD4(+) Tcells of healthy but not allergic subjects. FASEB J. 24, 5063-5072 (2010). www.fasebj.org