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.
Highlights
T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis
These findings are consistent with previous observations in murine Treg cells and the less efficient activation of store-operated Ca2+ entry (SOCE) by STIM2 compared to STIM124,31,32
These findings demonstrate that deletion of stromal interaction molecule 1 (STIM1) and STIM2 in mature tTregs by forkhead box P3 (Foxp3)-Cre does not interfere with the maintenance of Treg cells
Summary
T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. TTreg cells can further differentiate into specialized effector Treg subsets, such as tissue-resident, memory-like Treg cells that have important roles in the function of non-lymphoid organs[6,7], as well as T follicular regulatory (Tfr) cells that shape the quality and quantity of humoral immune responses during the germinal center (GC) reaction[8,9,10] These effector Treg cells differ significantly from Treg cells in secondary lymphoid organs because they acquire a tissue-specific gene expression program that includes transcription factors, homing receptors, and tissueadapted regulatory molecules, which are not or only weakly expressed in lymphoid tissue Treg cells[6,7]. In visceral adipose tissue (VAT), Treg cells express the adipose tissue-specific transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and modulate the insulin sensitivity of adipocytes[15]
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