Role of interferons (IFNs) in the differentiation of T peripheral helper (Tph) cells

CXCR5型 BCL6公司 白细胞介素21 生物 CXCL13型 细胞毒性T细胞 T细胞 分子生物学 免疫学 B细胞 免疫系统 抗体 趋化因子 体外 生发中心 趋化因子受体 生物化学
作者
Shuhei Tanemura,Hideto Tsujimoto,Noriyasu Seki,Shinji Kojima,Fumito Miyoshi,Kunio Sugahara,Keiko Yoshimoto,Katsuya Suzuki,Yuko Kaneko,Kenji Chiba,Tsutomu Takeuchi
出处
期刊:International Immunology [Oxford University Press]
卷期号:34 (10): 519-532 被引量:7
标识
DOI:10.1093/intimm/dxac026
摘要

Abstract T follicular helper (Tfh) cells and T peripheral helper (Tph) cells produce interleukin (IL)-21 and are thought to contribute to follicular and extra-follicular B-cell activation, respectively, in autoimmune diseases. It is known that programmed cell death-1 (PD-1)-positive CXCR5+ Tfh-like cells are differentiated from human naive CD4+ T cells by IL-12 plus transforming growth factor (TGF)-β. However, it remains unclear what cytokines are required for Tph differentiation. In this study, we found that interferon (IFN)-α and IFN-β reduce the frequency of Tfh-like cells under the IL-12 plus TGF-β condition, whereas they promote generation of PD-1+CXCR5−CD4+ T cells and secretion of IL-21, IFN-γ and CXCL13. Intracellular cytokine staining and T-cell–B-cell co-culture studies indicated that IFN-α promotes generation of IL-21+IFN-γ +CXCR5−CD4+ T cells thereby enhancing B-cell helper function. By IFN-α treatment, the mRNA levels of IL21, IFNG, CXCL13, CD244, SLAMF7, GZMB and PRDM1 were significantly up-regulated but BCL6 mRNA expression was down-regulated, suggesting a Tph-related gene expression pattern. On the other hand, IL-2-neutralization increased mRNA levels of IL21, CXCL13 and CXCR5, retained BCL6, but showed no clear effect on IFNG or PRDM1. RNA sequencing analyses revealed that PD-1hiCXCR5−CD4+ T cells prepared from in vitro culture show a Tph-related gene expression pattern similar with that of PD-1hiCXCR5− Tph cells obtained from the blood of patients with systemic lupus erythematosus. From our findings, it is highly probable that type I IFNs play a key role in differentiation of Tph cells and trigger Tph cell expansion in autoimmune diseases.
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