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  • Review Article
  • Published:

Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures

Nature Reviews Immunology volume 17, pages 112–129 (2017)Cite this article

Subjects

Key Points

  • Modulation of cellular immune and inflammatory processes — including antiviral defence mechanisms — relies crucially on cytokines, chemokines and their cell surface receptors.

  • Alternative versions of mammalian cytokine and chemokine receptors, widely known as decoy receptors, provide a key extension of immunoregulatory pathways in health and disease.

  • Decoy receptors typically mimic the binding principles that underlie the assembly of canonical complexes between protein effectors and cognate receptors.

  • Structural analyses and comparisons of canonical and decoy receptor complexes have revealed the diverse structural and mechanistic principles that underlie the immunomodulatory potency of decoy receptors.

  • Mechanisms of immune system subversion by viruses often feature virus-encoded decoy receptors that target host cytokines and chemokines.

  • Viral decoy receptors display structural and molecular mimicry of host receptors, but often use other mechanisms in addition to these 'in-built' features, including the use of novel protein scaffolds with functions that are unrelated to host proteins.

  • Structural and mechanistic annotations of mammalian and viral immunomodulatory decoy receptors may enable us to harness the therapeutic potential of such proteins and their complexes.

Abstract

Immune responses are regulated by effector cytokines and chemokines that signal through cell surface receptors. Mammalian decoy receptors — which are typically soluble or inactive versions of cell surface receptors or soluble protein modules termed binding proteins — modulate and antagonize signalling by canonical effector–receptor complexes. Viruses have developed a diverse array of molecular decoys to evade host immune responses; these include viral homologues of host cytokines, chemokines and chemokine receptors; variants of host receptors with new functions; and novel decoy receptors that do not have host counterparts. Over the past decade, the number of known mammalian and viral decoy receptors has increased considerably, yet a comprehensive curation of the corresponding structure–mechanism relationships has not been carried out. In this Review, we provide a comprehensive resource on this topic with a view to better understanding the roles and evolutionary relationships of mammalian and viral decoy receptors, and the opportunities for leveraging their therapeutic potential.

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Figure 1: Soluble mammalian decoy receptors derived from signalling receptors.
Figure 2: Soluble mammalian decoy receptor homologues and binding proteins.
Figure 3: Membrane-bound decoy receptors.
Figure 4: Virus-encoded cytokine and chemokine receptor homologues.
Figure 5: Herpesvirus-encoded and poxvirus-encoded binding proteins that do not have host counterparts.

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Acknowledgements

The authors gratefully acknowledge support from the Research Foundation Flanders, Belgium, which provided a research fellowship to J.F. and research grants to S.N.S. (G0597.10, G0643.07N and G0B7912N). S.N.S. is supported by a programme grant from the Flanders Institute for Biotechnology. The authors regret not being able to discuss and cite many valuable contributions in the field covered by this article because of space limitations.

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    Jan Felix & Savvas N. Savvides

  2. Department of Biochemistry and Microbiology, Ghent University, Ghent, 9052, Belgium

    Jan Felix & Savvas N. Savvides

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Virus-encoded cytokine and chemokine receptor homologues. (DOC 8240 kb)

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Herpesvirus-encoded and poxvirus-encoded binding proteins that do not have host counterparts. (DOC 1386 kb)

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Felix, J., Savvides, S. Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat Rev Immunol 17, 112–129 (2017). https://doi.org/10.1038/nri.2016.134

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