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SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation

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Science  21 Aug 2020:
Vol. 369, Issue 6506, pp. 984-988
DOI: 10.1126/science.aba6652

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SOSTDC1 for germinal center regulation

T follicular helper (TFH) cells are CD4+ T cells that facilitate B cell antibody production and B cell memory responses in the germinal centers (GCs) of lymphoid organs. These activities are in turn restrained by T follicular regulatory (TFR) cells, a population of T cells with unclear origins. Wu et al. now demonstrate that a subpopulation of TFH cells and fibroblastic reticular cells both produce sclerostin domain-containing protein 1 (SOSTDC1), which drives TFR cell generation by inhibiting Wnt–β-catenin signaling. In mice lacking the gene Sostdc1, TFR cell numbers were substantially decreased and GC responses were enhanced. These insights into TFR cell biology and GC regulation may have important implications for autoantibody-mediated diseases and the future development of vaccines and therapies for autoimmune disease.

Science, this issue p. 984

Abstract

Germinal center (GC) responses potentiate the generation of follicular regulatory T (TFR) cells. However, the molecular cues driving TFR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (TFH) cells and T–B cell border–enriched fibroblastic reticular cells, is developmentally required for TFR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing TFH cells as a distinct T cell population that develops after SOSTDC1 TFH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in TFH cells results in substantially reduced TFR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT–β-catenin axis and facilitates TFR cell differentiation.

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