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  • Review Article
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Balancing natural killer cell activation through paired receptors

Nature Reviews Immunology volume 15, pages 243–254 (2015)Cite this article

Subjects

Key Points

  • A family of molecules, including CD226, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and CD96, that bind nectin and nectin-like proteins has recently emerged as important regulators of natural killer (NK) cell functions.

  • This family of molecules regulates NK cell adhesion and cytotoxicity, immune synapse formation, cytokine secretion and crosstalk with dendritic cells.

  • This family of molecules has important roles in the pathophysiological processes of cancer, autoimmunity and viral infection.

  • The signalling properties of CD226, TIGIT and CD96 remain poorly characterized. Future work should discriminate the relative role of TIGIT and CD96 as negative regulators of CD226 activation in human and mouse immune responses.

  • Other well-defined paired receptors, such as the killer immunoglobulin-like receptor family and C-type lectin-like CD94–NKG2 receptor family molecules, control NK cell functions.

  • CD226, TIGIT and CD96 are crucial regulators of lymphocyte-mediated effector functions against tumours and may be promising new therapeutic targets for the treatment of malignancies.

Abstract

Natural killer (NK) cells are innate lymphocytes that are crucial for the control of infections and malignancies. NK cells express a variety of inhibitory and activating receptors that facilitate fine discrimination between damaged and healthy cells. Among them, a family of molecules that bind nectin and nectin-like proteins has recently emerged and has been shown to function as an important regulator of NK cell functions. These molecules include CD226, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), CD96, and cytotoxic and regulatory T cell molecule (CRTAM). In this Review, we focus on the recent advances in our understanding of how these receptors regulate NK cell biology and of their roles in pathologies such as cancer, infection and autoimmunity.

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Figure 1: Mode of interactions of nectin and nectin-like molecules.
Figure 2: Regulation of NK cell functions by CD226, CD96 and TIGIT.
Figure 3: TIGIT, CD226, CD96 and CRTAM ligand specificity and signalling.
Figure 4: Regulation of NK cell-mediated cancer immunosurveillance through CD155 expression.

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Acknowledgements

The authors thank members of their laboratory for contributions in this area. L.M. and M.J.S. are supported by a National Health and Medical Research Council of Australia Fellowship and Project Grant. L.M. is supported by the Association pour la Recherche Contre le Cancer.

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Authors and Affiliations

  1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, Queensland, Australia

    Ludovic Martinet & Mark J. Smyth

  2. Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1037, Cancer Research Center of Toulouse, Toulouse, F-31000, France

    Ludovic Martinet

  3. School of Medicine, University of Queensland, Herston, 4006, Queensland, Australia

    Mark J. Smyth

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Correspondence to Mark J. Smyth.

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M.J.S. holds a provisional patent “Immunoreceptor modulation for treating cancer and viral infections”. L.M. declares no competing interests.

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Martinet, L., Smyth, M. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 15, 243–254 (2015). https://doi.org/10.1038/nri3799

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