Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels

Martin Vaeth, Yin-Hu Wang, Miriam Eckstein, Jun Yang, Gregg J. Silverman, Rodrigo S. Lacruz, Kasthuri Kannan and Stefan Feske ()
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Martin Vaeth: New York University School of Medicine
Yin-Hu Wang: New York University School of Medicine
Miriam Eckstein: New York University College of Dentistry
Jun Yang: New York University School of Medicine
Gregg J. Silverman: New York University School of Medicine
Rodrigo S. Lacruz: New York University College of Dentistry
Kasthuri Kannan: New York University School of Medicine
Stefan Feske: New York University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.

Date: 2019
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DOI: 10.1038/s41467-019-08959-8

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