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COP9 signalosome subunit 8 is essential for peripheral T cell homeostasis and antigen receptor–induced entry into the cell cycle from quiescence

Nature Immunology volume 8, pages 1236–1245 (2007)Cite this article

Abstract

Engagement of antigen receptors triggers the proliferation and functional activation of lymphocytes. Here we report that T cell homeostasis and antigen-induced responses require the COP9 signalosome (CSN), a regulator of the ubiquitin-proteasome system. Conditional deletion of the CSN subunit Csn8 in peripheral T lymphocytes disrupted formation of the CSN complex, reduced T cell survival and proliferation in vivo and impaired antigen-induced production of interleukin 2. Moreover, Csn8-deficient T cells showed defective entry into the cell cycle from the G0 quiescent state. This phenotype was associated with a lack of signal-induced expression of cell cycle–related genes, including G1 cyclins and cyclin-dependent kinases, and with excessive induction of p21Cip1. Our data define a CSN-dependent pathway of transcriptional control that is essential for antigen-induced initiation of T cell proliferation.

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Figure 1: Csn8 is essential for mammalian embryonic development.
Figure 2: Loss of Csn8 impairs peripheral T cell homeostasis.
Figure 3: Defective activation of Csn8-deficient T cells.
Figure 4: Csn8 is required for TCR-induced proliferation.
Figure 5: Quiescent Csn8-deficient MEFs fail to reenter the cell cycle.
Figure 6: Proximal TCR signaling events.
Figure 7: Expression of cell cycle regulators after TCR activation.
Figure 8: Defects in transcriptional regulation of cell cycle–related genes.

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Acknowledgements

We thank R. Reed (Harvard Medical School) for anti-SF3a; H. Zhang (Yale Medical School) for anti–cyclin A; N. Colburn (National Institutes of Health) for anti-Pdcd4; R. Pardi for communicating unpublished data; K. Lykke-Andersen for contributions to the design and initial construction of the targeting plasmid; and D. Chamovitz and R. Pardi for critical reading of the manuscript and discussions. Supported by the National Institutes of Health (R01-GM61812 to N.W., and R37-GM047850 to X.W.D.), the Arthritis Foundation (H.C.) and the Howard Hughes Medical Institute (R.A.F.).

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  1. Suchithra Menon and Hongbo Chi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, 06511, Connecticut, USA

    Suchithra Menon, Huiyong Zhang, Xing Wang Deng & Ning Wei

  2. Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Hongbo Chi & Richard A Flavell

  3. Department of Immunology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Hongbo Chi

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Contributions

S.M. and H.C. designed and did T cell and MEF experiments; H.Z. and S.M. did Chromatin IP. S.M. together with the technical staff in R.A.F. lab generated the knockout strain. S.M. and N.W. bred mouse colonies and characterized the embryos. H.C., S.M. and N.W. analyzed data and wrote the manuscript; N.W. R.A.F. and X.W.D. provided advice and overall direction. The laboratories of N.W. and R.A.F. contributed equally to this study.

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Correspondence to Ning Wei.

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Menon, S., Chi, H., Zhang, H. et al. COP9 signalosome subunit 8 is essential for peripheral T cell homeostasis and antigen receptor–induced entry into the cell cycle from quiescence. Nat Immunol 8, 1236–1245 (2007). https://doi.org/10.1038/ni1514

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