Regulation of T cell survival through coronin-1–mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering

Abstract

T cell homeostasis is essential for the functioning of the vertebrate immune system, but the intracellular signals required for T cell homeostasis are largely unknown. We here report that the WD-repeat protein family member coronin-1, encoded by the gene Coro1a, is essential in the mouse for T cell survival through its promotion of Ca2+ mobilization from intracellular stores. Upon T cell receptor triggering, coronin-1 was essential for the generation of inositol-1,4,5-trisphosphate from phosphatidylinositol-4,5-bisphosphate. The absence of coronin-1, although it did not affect T cell development, resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival. We conclude that coronin-1, through activation of Ca2+ release from intracellular stores, is an essential regulator of peripheral lymphocyte survival.

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Figure 1: T cell cytoskeleton and F-actin dynamics in the presence and absence of coronin-1.
Figure 2: T cell proliferation and cycling in the presence and absence of coronin-1.
Figure 3: T cell signaling, InsP3 generation and localization of signaling molecules.
Figure 4: PtdIns(4,5)P2 localization and Ca2+ mobilization in wild-type and coronin-1–deficient T cells.
Figure 5: Thymocyte coronin-1 and Ca2+ flux.
Figure 6: Signaling pathways in wild-type and coronin-1–deficient cells upon TCR and PLC activation.
Figure 7: Interaction of Coronin-1 and PLC-γ1.

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Acknowledgements

We thank L. Kuhn for assistance with two-dimensional SDS-PAGE and J. Kirberg, K. Huygen, H. Korf, V. Jaeggin, E. Teixeiro, M. Daniels, E. Palmer and P. Demougin for help and discussions. Supported by the German Research Council (SFB 497-B5 to H.-R.R.) and the Kanton Basel-Stadt as well as the Swiss National Science Foundation (to J.P.).

Author information

P.M. performed the experiments unless stated otherwise; J.M. generated the coronin-1–deficient mice and performed their phenotypic analysis (shown in Supplementary Figs. 1, 2, 3 and Fig. 2a) with contributions from I.A., B.C., C.B., R.C., H.-R.R. and A.G.R.; J.G. generated the siRNA used in Jurkat T cells and R.J. performed the video microscopy, m-3M3FBS experiments and PtdIns(4,5)P2 analysis as well as the experiments presented in Figures 1b and 3g; R.J. and B.C. together with P.M. performed the experiments shown in Supplementary Figure 6; J.P. coordinated as well as supervised the project and prepared the manuscript.

Correspondence to Jean Pieters.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figures 1–8, Supplementary Table 1 (PDF 2295 kb)

Supplementary Video 1

Normal cell spreading of wild-type T cells seeded on polylysine coated slides (control); time-lapse images were acquired every 10 seconds for 30 minutes. (MOV 929 kb)

Supplementary Video 2

Normal cell spreading of Coronin-1-deficient T cells seeded on polylysine coated slides (control); time-lapse images were acquired every 10 seconds for 30 minutes. (MOV 909 kb)

Supplementary Video 3

Normal TCR-mediated cell spreading of wild-type T cells seeded on anti-CD3 + anti-CD28 coated slides; time-lapse images were acquired every 10 seconds for 30 minutes. (MOV 2048 kb)

Supplementary Video 4

Normal TCR-mediated cell spreading of Coronin-1-deficient T cells seeded on anti-CD3 + anti-CD28 coated slides; time-lapse images were acquired every 10 seconds for 30 minutes. (MOV 1903 kb)

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Mueller, P., Massner, J., Jayachandran, R. et al. Regulation of T cell survival through coronin-1–mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering. Nat Immunol 9, 424–431 (2008). https://doi.org/10.1038/ni1570

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