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Dr. Xindong Liu’s team provides SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation

 

With germinal center (GC) reactions, thymus-derived Treg cells give rise to follicular regulatory T (Tfr) cells. Tfr cells negatively regulate the central axis of “follicular helper T (Tfh) cells – B cells – antibodies” humoral immunity, which not only maintain the normal humoral immune responses, but prevent the occurrence of antibody-mediated autoimmune diseases. However, how nTreg cells differentiate into Tfr cells remains unclear.

Dr. Xindong Liu’s group from First Affiliated Hospital of Army Medical University discovered a distinctive subpopulation of Tfh cells and defined as SOSTDC1+Tfh cells. Functionally, unlike SOSTDC1–Tfh cells, SOSTDC1+Tfh cells were unable to help B cells for antibody production, and promoted differentiation of Tfr cells by secreting protein SOSTDC1, and regulated GC response with negative feedback. We found that Tfh cells selectively expressed SOSTDC1 and existed as a unique Tfh cell population, SOSTDC1+Tfh cells. SOSTDC1 protein was highly expressed in Tfh and fibroblastic reticular cells that localized at the T – B cell border regions. Further single-cell RNA-seq analysis demonstrated SOSTDC1+Tfh cells developed from SOSTDC1–Tfh cells. Unlike classical SOSTDC1–Tfh cells, SOSTDC1+Tfh cells lost their ability to provide B cells help. In influenza virus infection model and specific antigen immunized model in Sostdc1 knockout mice, we found that Sostdc1 deficiency largely increased GC responses: enhanced GC B cell numbers concomitant with reduced Tfr cell numbers. Further bone marrow chimeras revealed that Tfh-derived SOSTDC1 was critical for Tfr cell formation.

The molecular mechanism of SOSTDC1 promoting Tfr cell differentiation was further explored. Transcriptome analysis demonstrated overexpression of WNT ligand genes in SOSTDC1–Tfh cells, whereas WNT-antagonistic genes were elevated in SOSTDC1+Tfh cells. Furthermore, defective Tfr cells observed in Sostdc1 deficiency significantly upregulated the expression of effector cytokines IL-4, IL-5 and IL-6, and predominantly augmented activation of WNT/β-catenin signaling axis, suggesting that SOSTDC1 expressing-Tfh cells could promote Tfr cell differentiation.

On August 21th, 2020, the article “SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation” was published in Science Journal. They provide a distinctive subpopulation of Tfh cells and defined as SOSTDC1+Tfh cells. It is elucidated that SOSTDC1+Tfh cells could promote Tfr cell differentiation and regulates antibody production with negative feedback. These findings not only provide a theoretical basis for vaccine development strategies, but also provide a new perspective for drug development of autoimmune diseases and strategies to improve antiviral infection.

Dr. Xindong Liu, Dr. Xiu-wu Bian, and Dr. Yan Wang from Institute of Pathology of First Affiliated Hospital, Army Medical University, are co-corresponders. Dr. Xin Wu is the first author.

Links: https://science.sciencemag.org/content/369/6506/984