TGF-[beta] induces the differentiation of human CXCL13-producing CD4+ Tￂ 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-[beta] induces the differentiation of human...

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Bibliographic Details
Published in:European journal of immunology 2016-02, Vol.46 (2), p.360
Main Authors: Kobayashi, Shio, Watanabe, Takeshi, Suzuki, Ryo, Furu, Moritoshi, Ito, Hiromu, Ito, Juichi, Matsuda, Shuichi, Yoshitomi, Hiroyuki
Format: Article
Language:English
Subjects:
B-cell lymphoma
Bcl-6 protein
CD25 antigen
CD4 antigen
CXCL13 protein
CXCR5 protein
Effector cells
Foxp3 protein
Immunological memory
Inflammation
Interleukin 2
Interleukin 2 receptors
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoma
Memory cells
Neutralization
Rheumatoid arthritis
Stat5 protein
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Summary: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-[beta] induces the differentiation of human CXCL13-producing CD4+ T cells from naïve CD4+ T cells. The TGF-[beta]-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-2R[alpha]) 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 naïve 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-[beta] signaling but not via FoxP3, and exert their function in IL-2-limited but TGF-[beta]-rich and proinflammatory cytokine-rich inflammatory conditions.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201546043