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New inhibitory signaling by CTLA-4

Nature Immunology volume 15, pages 408–409 (2014)Cite this article

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CTLA-4 is a potent inhibitor of T cell population expansion. The PIX-GIT2-PAK2 complex is recruited to the cytoplasmic domain of CTLA-4 via the kinase PKC-η, which suggests a previously unrecognized aspect of signal transduction via CTLA-4 in immunoregulation.

CTLA-4 is a receptor expressed by effector T cells and regulatory T cells (Treg cells) that, after engagement of its ligand, suppresses the population expansion of T cells. It can function in a cell-extrinsic way, by impairing the ability of antigen-presenting cells (APCs) to activate T cells, as well as in a cell-intrinsic way, by attenuating signaling via T cells. In this issue of Nature Immunology, Kong et al. show that CTLA-4 constitutively associates with the kinase PKC-η selectively in Treg cells1. PKC-η then recruits and activates the PIX-GIT2-PAK2 complex, a large scaffold with established involvement in the endocytosis of receptors, actin dynamics and activation of the signaling protein PLC-γ. In the absence of PKC-η, conjugates of Treg cells and APCs become more stable, which prevents efficient sequential interaction of Treg cells with many APCs.

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Figure 1: Subcellular constraints of CTLA-4 signaling.

Katie Vicari

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Authors and Affiliations

  1. Christoph Wülfing, Helen M. Tunbridge and David C. Wraith are with the School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.,

    Christoph Wülfing, Helen M Tunbridge & David C Wraith

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  1. Christoph Wülfing
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  2. Helen M Tunbridge
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  3. David C Wraith
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Correspondence to Christoph Wülfing.

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Wülfing, C., Tunbridge, H. & Wraith, D. New inhibitory signaling by CTLA-4. Nat Immunol 15, 408–409 (2014). https://doi.org/10.1038/ni.2870

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