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A serine protease inhibitor induces type 1 regulatory T cells through IFN-γ/STAT1 signaling

Cellular & Molecular Immunology volume 17, pages 1004–1006 (2020)Cite this article

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Type 1 regulatory T cells (CD4+Foxp3−LAG3+CD49b+), or Tr1 cells, have a remarkable capacity to suppress autoimmune inflammation through IL-10.1 Although the signals that lead to Tr1-cell differentiation are not completely elucidated, it is known that IL-27 plays a major role in this phenomenon.2 However, committed inflammatory Th17 cells are resistant to IL-27,3 making their effectiveness in the clinic limited. Thus, there is an unmet need to identify new drugs that stimulate Tr1-cell development. We have shown that a soybean-derived serine protease inhibitor, Bowman-Birk inhibitor (BBI), dramatically suppressed experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS), by inducing IL-10.4 However, the immunomodulatory mechanism by which BBI induces IL-10 and suppresses EAE has not been elucidated.

Although IL-27 potently induces Tr1 cells,2 we found that BBI induced IL-10 and IFN-γ production in WT and IL-27R−/− CD4+ T cells (Fig. 1e). BBI did not increase the expression of IL-27 subunits (p28 and EBI-3) (data not shown). These data show that BBI induces IL-10 in an IL-27-independent manner. Additionally, Stat-1 is downstream of IL-27R signaling and induces IL-10- and Tr1-cell differentiation.2 Moreover, it is known that T-bet−/− and Stat-1−/− cells produce more IL-10 than WT cells under homeostatic conditions.7,8 We found that BBI failed to upregulate IL-10 production in Stat-1−/− cells (Fig. 1f). In T-bet−/− cells, BBI induced IL-10 but at significantly lower levels than in WT cells (Fig. 1f).

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Fig. 1: BBI induces Tr1 cells.

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Acknowledgements

This work was supported by NIH grant R01AT005322, R01AI124386 to A.R. The authors thank Katherine Regan for editorial assistance.

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  1. Farinaz Safavi

    Present address: NINDS, National Institute of Health, Bethesda, MD, USA

Authors and Affiliations

  1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

    Farinaz Safavi, Rodolfo Thome, Zichen Li, Limei Wang, Javad Rasouli, Bogoljub Ciric, Guang-Xian Zhang & Abdolmohamad Rostami

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  1. Farinaz Safavi
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Correspondence to Abdolmohamad Rostami.

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Safavi, F., Thome, R., Li, Z. et al. A serine protease inhibitor induces type 1 regulatory T cells through IFN-γ/STAT1 signaling. Cell Mol Immunol 17, 1004–1006 (2020). https://doi.org/10.1038/s41423-019-0354-6

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