TGF-β induces the differentiation of human CXCL13-producing CD4(+) T cells.

In the ectopic lymphoid-like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4+ T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF-β induces the differentiation of human CXCL13-producing CD4+ T cells from naive CD4+ T cells. The TGF-β-induced CXCL13-producing CD4+ T cells do not express CXCR5, B-cell lymphoma 6 (BCL6), and other Tfh-cell markers. Furthermore, expression levels of CD25 (IL-2Rα) in CXCL13-producing CD4+ T cells are significantly lower than those in FoxP3+ in vitro induced Treg cells. Consistent with this, neutralization of IL-2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4+ T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naive CD4+ T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13-producing CD4+ T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13-producing CD4+ T cells. Our findings demonstrate that CXCL13-producing CD4+ T cells lacking Tfh-cell features differentiate via TGF-β signaling but not via FoxP3, and exert their function in IL-2-limited but TGF-β-rich and proinflammatory cytokine-rich inflammatory conditions.