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Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance

Abstract

Store-operated Ca2+ entry through calcium release–activated calcium channels is the chief mechanism for increasing intracellular Ca2+ in immune cells. Here we show that mouse T cells and fibroblasts lacking the calcium sensor STIM1 had severely impaired store-operated Ca2+ influx, whereas deficiency in the calcium sensor STIM2 had a smaller effect. However, T cells lacking either STIM1 or STIM2 had much less cytokine production and nuclear translocation of the transcription factor NFAT. T cell–specific ablation of both STIM1 and STIM2 resulted in a notable lymphoproliferative phenotype and a selective decrease in regulatory T cell numbers. We conclude that both STIM1 and STIM2 promote store-operated Ca2+ entry into T cells and fibroblasts and that STIM proteins are required for the development and function of regulatory T cells.

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Figure 1: STIM1 is a predominant effector of store-operated Ca2+ entry into T cells.
Figure 2: Both STIM1 and STIM2 reconstitute store-operated Ca2+ entry and cytokine production in STIM1-deficient T cells and MEFs.
Figure 3: Loss of STIM2 affects sustained Ca2+ influx and the late phase of NFAT1 nuclear localization.
Figure 4: STIM1-deficient but not STIM2-deficient T cells lack ICRAC.
Figure 5: Impaired Ca2+ influx, cytokine production and proliferation in double-knockout T cells.
Figure 6: Double deficiency in STIM1 and STIM2 disrupts peripheral T cell homeostasis.
Figure 7: Absence of STIM1 and STIM2 impairs the development of Treg cells.
Figure 8: Adoptive transfer of wild-type Treg cells suppresses the lymphoproliferative phenotype of double-knockout mice.

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Acknowledgements

We thank K. Rajewsky and members of the Rajewsky lab for help with blastocyst injection of embryonic stem cells; M.E. Pipkin and A.Y. Rudensky for comments and discussions; Y. Gwack for purification of anti-STIM2; and B. Baust for help in establishing the NFAT-translocation assay. Supported by the National Institutes of Health (A.R., S.F. and M.P.), Juvenile Diabetes Research Foundation (A.R.), March of Dimes Foundation (S.F.), Uehara Memorial Foundation (M.O.) and Canadian Institutes of Health Research (S.S.).

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M.O. generated the gene-disrupted mice and did the bulk of the experiments; M.Y., W.C. and M.P. were responsible for all electrophysiology experiments; S.S. established the NFAT translocation assay; E.L. did the immunohistochemistry; S.F. did the single-cell Ca2+ imaging for T cells and codirected the project with P.G.H. and A.R.; and M.O., S.F., P.G.H. and A.R. wrote the manuscript together.

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Correspondence to Stefan Feske or Anjana Rao.

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P.G.H., S.F. and A.R. are scientific founders of Calcimedica, a company whose research on immune therapies includes a focus on inhibitors of the STIM-ORAI pathway.

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Oh-hora, M., Yamashita, M., Hogan, P. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat Immunol 9, 432–443 (2008). https://doi.org/10.1038/ni1574

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