Sustained store-operated calcium entry utilizing activated chromatin state leads to instability in iTregs
Huiyun Lyu,
Guohua Yuan,
Xinyi Liu,
Xiaobo Wang,
Shuang Geng,
Tie Xia,
Xuyu Zhou,
Yinqing Li,
Xiaoyu Hu,
Yan Shi
Affiliations
Huiyun Lyu
Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
Guohua Yuan
IDG/McGovern Institute for Brain Research and School of Pharmaceutical Sciences, Tsinghua University, Beijing, China; MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
Xinyi Liu
Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
Xiaobo Wang
Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
Shuang Geng
Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Canada
Tie Xia
Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
Xuyu Zhou
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Yinqing Li
IDG/McGovern Institute for Brain Research and School of Pharmaceutical Sciences, Tsinghua University, Beijing, China; MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Canada
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 Foxp3 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 (TH) 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.