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
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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