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STIM1-Independent T Cell Development and Effector Function In Vivo¹

Niklas Beyersdorf^2,*, Attila Braun^2,, Timo Vögtle, David Varga-Szabo, Ronmy Rivera Galdos, Stephan Kissler, Thomas Kerkau^* and Bernhard Nieswandt^3,,

^* Institute for Virology and Immunobiology, Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, and Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany

Store-operated Ca²⁺ entry (SOCE) is believed to be of pivotal importance in T cell physiology. To test this hypothesis, we generated mice constitutively lacking the SOCE-regulating Ca²⁺ sensor stromal interaction molecule 1 (STIM1). In vitro analyses showed that SOCE and Ag receptor complex-triggered Ca²⁺ flux into STIM1-deficient T cells is virtually abolished. In vivo, STIM1-deficient mice developed a lymphoproliferative disease despite normal thymic T cell maturation and normal frequencies of CD4⁺Foxp3⁺ regulatory T cells. Unexpectedly, STIM1-deficient bone marrow chimeric mice mounted humoral immune responses after vaccination and STIM1-deficient T cells were capable of inducing acute graft-versus-host disease following adoptive transfer into allogeneic hosts. These results demonstrate that STIM1-dependent SOCE is crucial for homeostatic T cell proliferation, but of much lesser importance for thymic T cell differentiation or T cell effector functions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Rudolf Virchow Center, the Deutsche Forschungsgemeinschaft (Ni 556/7-1 to B.N.), and the Wilhelm Sander-Stiftung (2005.133.1).

² N.B. and A.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Bernhard Nieswandt, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Versbacherstrasse 9, 97078 Würzburg, Germany. E-mail address: bernhard.nieswandt{at}virchow.uni-wuerzburg.de

⁴ Abbreviations used in this paper: ER, endoplasmic reticulum; aGvHD, acute graft-versus-host disease; BMc mice, bone marrow chimeric; CRAC, calcium release-activated calcium; KLH, keyhole limpet hemocyanin; SOCE, store-operated calcium entry; STIM1/STIM2, stromal interaction molecule 1/2; TCD, T cell-depleted bone marrow; Treg, regulatory T; wt, wild type; CBA, cytometric bead array; BM, bone marrow; TG, thapsigargin; Tind, indicator T cell; FSC, forward scatter; SSC, side scatter.

⁵ The online version of this article contains supplemental material.