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Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc–dependent pathway

Nature Immunology volume 2, pages 698–704 (2001)Cite this article

Abstract

T lymphocytes circulate in a quiescent state until they encounter cognate antigen bound to the surface of an antigen-presenting cell. The molecular pathways that regulate T cell quiescence remain largely unknown. Here we show that forced expression of the lung Krüppel-like transcription factor (LKLF) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation, reduced cell size and protein synthesis and decreased surface expression of activation markers. Conversely, LKLF-deficient peripheral T cells produced by gene targeting showed increased proliferation, increased cell size and enhanced expression of surface activation markers in vivo. LKLF appeared to function, at least in part, by decreasing expression of the proto-oncogene encoding c-Myc. Forced expression of LKLF was associated with markedly decreased c-Myc expression. In addition, many effects of LKLF expression were mimicked by expression of the dominant-negative MadMyc protein and rescued by overexpression of c-Myc. Thus, LKLF is both necessary and sufficient to program quiescence in T cells and functions, in part, by negatively regulating a c-Myc–dependent pathway.

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Figure 1: Expression of LKLF in Jurkat cells with the use of a tetracycline-inducible system.
Figure 2: LKLF inhibits T cell proliferation.
Figure 3: The inhibitory effects of LKLF on T cell proliferation are reversible and are not due to the induction of apoptosis
Figure 4: Effects of LKLF expression on Jurkat cell cycle progression.
Figure 5: Effects of LKLF expression on T cell macromolecular synthesis, cell size and surface phenotype.
Figure 6: LKLF decreases c-Myc mRNA and protein expression in Jurkat cells.
Figure 7: LKLF functions via a c-Myc–dependent pathway in Jurkat cells.
Figure 8: Effects of LKLF, MadMyc and c-Myc expression on quiescence in CCRF-CEM cells.

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Acknowledgements

We thank M. Vander Heiden and C. Thompson for ATP measurements and helpful discussions; K. Sigrist, R. Wei, Y. Lin for technical assistance; J. Auger, A. Lin, I. Ho for technical advice; R. Bernards for pCMVMadMyc; R. Eisenman for pSP271myc; H. Bujard for Tet-inducible plasmids; G. Nolan for pRVNL3; A. Krumm for ΔP1CAT; D. Marshall for pGEMAdEF1; C. Ting for the use of data before publication; J. Bluestone, A. Ma, M. Peter, D. Strauss and J. Quintans for helpful discussions; E. Kaji, J. Lepore, G. Huggins and G. Reed for critical reading of the manuscript. Supported by a grant from N.I.H. (to J. M. L.) and by NIGMS (A. F. B.).

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Authors and Affiliations

  1. Committee on Immunology, University of Chicago, Chicago, 60637, IL, USA

    Anne F. Buckley & Jeffrey M. Leiden

  2. Harvard School of Public Health, Boston, 02115, MA, USA

    Anne F. Buckley

  3. Pritzker School of Medicine, University of Chicago, Chicago, 60637, IL, USA

    Chay T. Kuo

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Correspondence to Jeffrey M. Leiden.

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Buckley, A., Kuo, C. & Leiden, J. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc–dependent pathway. Nat Immunol 2, 698–704 (2001). https://doi.org/10.1038/90633

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