Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-κB and NFAT


Pre-T cell antigen receptor (pre-TCR) signaling plays a crucial role in the development of immature T cells. Although certain aspects of proximal pre-TCR signaling have been studied, the intermediate signal transducers and the distal transcription modulators have been poorly characterized. We report here a correlation between pre-TCR signaling and a biphasic rise in the cytosolic Ca2+ concentration. In addition, we show that constitutive pre-TCR signaling is associated with an increased rate of Ca2+ influx through store-operated plasma membrane Ca2+ channels. We show also that the biphasic nature of the observed pre-TCR–induced rise in cytosolic Ca2+ differentially modulates the activities of the transcription factors NF-κB and NFAT in developing T cells.

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Figure 1: NF-κB is activated at the β-selection checkpoint.
Figure 2: Pre-TCR expression induces activation of NF-κB.
Figure 3: Essential role of NFAT activation during β-selection.
Figure 4: The nature of the pre-TCR-induced biphasic [Ca2+]i increase in pre-TCR+ cells.
Figure 5: Intracellular Ca2+ store depletion-activated Ca2+ influx is reduced in SCIET27 versus SCB29 cells Representative traces of SOCs mediated a rise in (a) [Ca2+]i in WT CD25CD44 and RAG-2−/− CD25+CD44 thymocytes as well as in (b) SCB29 and SCIET27 cells.
Figure 6: Effects of different Ca2+ mobilization inhibitors on the activation of NF-κB and NFAT in the SCB29 cell line.
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We thank E. A. Smith for help with the preparing the manuscript, S. Hoeflinger for technical assistance and S. Korsmeyer, V. Boussiotis, S. Zinkel, S. Simeonidis and N. Danial for material and valuable discussions. Supported by National Institutes of Health grant number R01AI45846 (to H. v. B.) and the Eugenia Spanopoulou Irvington Institute (to I. A.). C. B. is supported by the Division of Medical Sciences of Harvard University.

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Correspondence to Harald von Boehmer.

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Aifantis, I., Gounari, F., Scorrano, L. et al. Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-κB and NFAT. Nat Immunol 2, 403–409 (2001).

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