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Bcl10 is required for the development and suppressive function of Foxp3+ regulatory T cells

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Abstract

Foxp3+ regulatory T (Treg) cells play a critical role in peripheral tolerance. Bcl10, acting as a scaffolding protein in the Carma1-Bcl10-Malt1 (CBM) complex, has a critical role in TCR-induced signaling, leading to NF-κB activation and is required for T-cell activation. The role of Bcl10 in conventional T (Tconv) cells has been well characterized; however, the role of Bcl10 in the development of Treg cells and the maintenance of the suppressive function and identity of these cells has not been well characterized. In this study, we found that Bcl10 was required for not only the development but also the function of Treg cells. After deleting Bcl10 in T cells, we found that the development of Treg cells was significantly impaired. When Bcl10 was specifically deleted in mature Treg cells, the suppressive function of the Treg cells was impaired, leading to lethal autoimmunity in Bcl10fl/flFoxp3cre mice. Consistently, in contrast to WT Treg cells, Bcl10-deficient Treg cells could not protect Rag1-deficient mice from T-cell transfer-induced colitis. Furthermore, Bcl10-deficient Treg cells downregulated the expression of a series of Treg-cell effector and suppressive genes and decreased effector Treg-cell populations. Moreover, Bcl10-deficient Treg cells were converted into IFNγ-producing proinflammatory cells with increased expression of the transcription factors T-bet and HIF-1α. Together, our study results provide genetic evidence, indicating that Bcl10 is required for the development and function of Treg cells.

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Acknowledgements

We thank Dr. Chen Dong for providing the Rag1−/−, CD4cre and Foxp3cre-YFP mice and Dr. Li Wu for providing the CD45.1+ mice. We thank the Laboratory Animal Research Center of Tsinghua University for help with microinjections. This work was supported by grants from the National Natural Science Foundation of China (81570211 to X.L. and 31670904 to X.Z.) and funding from the Tsinghua University-Peking University Jointed Center for Life Sciences (to X.L.).

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  1. Department of Basic Medical Sciences and Institute for Immunology, Tsinghua University School of Medicine, Beijing, 100084, China

    Dandan Yang, Xueqiang Zhao & Xin Lin

  2. Tsinghua University-Peking University Jointed Center for Life Sciences, Beijing, 100084, China

    Xin Lin

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  1. Dandan Yang
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Yang D performed all of the experiments, and Lin X and Zhao X directed the experiments. Yang D, Zhao X, and Lin X wrote the manuscript.

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Correspondence to Xin Lin.

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All institutional and national guidelines for the care and use of laboratory animals were followed. The authors declare no competing interests.

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Yang, D., Zhao, X. & Lin, X. Bcl10 is required for the development and suppressive function of Foxp3+ regulatory T cells. Cell Mol Immunol 18, 206–218 (2021). https://doi.org/10.1038/s41423-019-0297-y

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