FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

Wang, X.; Geng, S.; Meng, J.; Kang, N.; Liu, X.; Xu, Y.; Lv, H.; Xu, X.; Song, X.; Zhang, B.; Nuerbulati, N.; Zhang, Z.; Zhai, D.; Mao, X.; Sun, R.; Wang, R.; Guo, J.; Chen, S. R. W.; Zhou, X.; Xia, T.; Qi, H.; Hu, X.; Shi, Y.

doi:10.1101/2022.05.02.490213

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bioRxiv · 10.1101/2022.05.02.490213

FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

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Abstract

The suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2. Reduced RyR2 shuts down basal Ca2+ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+ T cell pool to become immune suppressive, and behave in the same manner as FoxP3+ Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+ T cells rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression. One Sentence SummaryCalcium channel RyR2 dictates Treg adhesion-based suppression

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Wang, X., Geng, S., Meng, J., Kang, N., Liu, X., Xu, Y., Lv, H., Xu, X., Song, X., Zhang, B., Nuerbulati, N., Zhang, Z., Zhai, D., Mao, X., Sun, R., Wang, R., Guo, J., Chen, S. R. W., Zhou, X., Xia, T., Qi, H., Hu, X., Shi, Y.. 2022-05-03. FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells. https://doi.org/10.1101/2022.05.02.490213

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