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Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling

Nature Immunology volume 3, pages 251–258 (2002)Cite this article

Abstract

T cell receptor (TCR) stimulation activates the small GTPase Rap1A, which is reported to antagonize Ras signaling and induces T cell anergy. To address its role in vivo, we generated transgenic mice that constitutively expressed active Rap1A within the T cell lineage. We found that active Rap1A did not interfere with the Ras signaling pathway or antagonize T cell activation. Instead of anergy, the T lymphocytes that constitutively expressed active Rap1A showed enhanced TCR-mediated responses, both in thymocytes and mature T cells. In addition, Rap1A activation was sufficient to induce strong activation of the β1 and β2 integrins via an avidity-modulation mechanism. This shows that, far from playing an inhibitory role during T cell activation, Rap1A positively influences T cells by augmenting lymphocyte responses and directing integrin activation.

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Figure 1: Generation of constitutively active Rap1A-transgenic mice.
Figure 2: Constitutively active Rap1A does not block thymocyte development or T cell maturation.
Figure 3: Erk activation is normal in V12Rap1A-transgenic T cells.
Figure 4: V12Rap1A-transgenic T cells proliferate in response to mitogenic stimulation.
Figure 5: Constitutively active Rap1A augments, not diminishes, in vivo thymocyte responses.
Figure 6: Constitutively active Rap1A enhances in vitro thymocyte and T cell responses.
Figure 7: V12Rap1A induces integrin-mediated thymocyte adhesion.
Figure 8: Constitutively active Rap1A induces avidity modulation of LFA-1.

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Acknowledgements

We thank I. Rosewell for injection of transgenic constructs; T. Davies, P. Haskings, C. Tate and C. Young for animal care; P. Stanley for preparation of soluble mouse ICAM-1; A. Nicol, H. Hinton and P. Costello for helping with confocal microscopy; and K. Reedquist and H. Bos (Utrecht, the Netherlands) for constructs and discussions. Supported by the Imperial Cancer Research Fund.

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  1. Lymphocyte Activation Laboratory, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Eric Sebzda, Tamara Tugal & Doreen Ann Cantrell

  2. Leukocyte Adhesion Laboratory, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Madelon Bracke & Nancy Hogg

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Correspondence to Doreen Ann Cantrell.

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Sebzda, E., Bracke, M., Tugal, T. et al. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nat Immunol 3, 251–258 (2002). https://doi.org/10.1038/ni765

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