Sustained store-operated calcium entry utilizing activated chromatin state leads to instability in iTregs

• Published in: eLife Vol. 12
• Main Authors: Lyu, Huiyun, Yuan, Guohua, Liu, Xinyi, Wang, Xiaobo, Geng, Shuang, Xia, Tie, Zhou, Xuyu, Li, Yinqing, Hu, Xiaoyu, Shi, Yan
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 06-12-2023; eLife Sciences Publications Ltd
• Subjects: Calcium - metabolism; calcium signal; Cell activation; Cell therapy; Chromatin; Chromatin - metabolism; chromatin accessibility; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Genes; Genotype & phenotype; Immunoregulation; Inflammation; Instability; iTreg; Lymphocytes; Methylation; NF-AT protein; NFAT; Nuclear transport; Phenotypes; Signal Transduction; Spectrum analysis; stability; T cell receptors; T cells; T-Lymphocytes, Regulatory; Thymus gland; Transcription activation; Transcription factors; Treg; mouse; genetics; inflammation; iTreg; Treg; chromatin accessibility; genomics; calcium signal; immunology; stability; NFAT
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88874

Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of
CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here, we show that upon TCR (T cell receptor) triggering, SOCE (store-operated calcium entry) and NFAT (nuclear factor of activated T cells) nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed-opened T helper (T
) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus, our study adds two new layers, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.