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

• Published in: International immunology 2022-09, Vol.34 (10), p.519-532
• Main Authors: Tanemura, Shuhei, Tsujimoto, Hideto, Seki, Noriyasu, Kojima, Shinji, Miyoshi, Fumihiko, Sugahara, Kunio, Yoshimoto, Keiko, Suzuki, Katsuya, Kaneko, Yuko, Chiba, Kenji, Takeuchi, Tsutomu
• Format: Article
• Language: English
• ISSN: 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxac026

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. Type I IFNs promote Tph-cell generation Graphical Abstract