Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Functional categories of immune inhibitory receptors

Nature Reviews Immunology volume 20, pages 771–780 (2020)Cite this article

Subjects

Abstract

The human genome encodes more than 300 potential immune inhibitory receptors. The reason for this large number of receptors remains unclear. We suggest that inhibitory receptors operate as two distinct functional categories: receptors that control the signalling threshold for immune cell activation and receptors involved in the negative feedback of immune cell activation. These two categories have characteristic receptor expression patterns: ‘threshold’ receptors are expressed at steady state and their expression remains high or is downregulated upon activation, whereas ‘negative feedback’ receptors are induced upon immune cell activation. We use mathematical models to illustrate their possible modes of operation in different scenarios for different purposes. We discuss how this categorization may impact the choice of therapeutic targets for immunotherapy of malignant, infectious and autoimmune diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Different categories of inhibitory receptors based on the regulation of inhibitory ligand and receptor expression.
Fig. 2: Schematic representation of the different mathematical models.
Fig. 3: Threshold receptors prevent unnecessary responses.
Fig. 4: Disinhibition can be beneficial compared with constant inhibition.
Fig. 5: Negative feedback is beneficial in systems with delay.

Similar content being viewed by others

References

  1. Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Olde Nordkamp, M. J., Koeleman, B. P. & Meyaard, L. Do inhibitory immune receptors play a role in the etiology of autoimmune disease? Clin. Immunol. 150, 31–42 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Colonna, M. Immunoglobulin superfamily inhibitory receptors: from natural killer cells to antigen-presenting cells. Res. Immunol. 148, 169–171 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Daeron, M., Jaeger, S., Du Pasquier, L. & Vivier, E. Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol. Rev. 224, 11–43 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. van der Vlist, M., Kuball, J., Radstake, T. R. & Meyaard, L. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat. Rev. Rheumatol. 12, 593–604 (2016).

    Article  PubMed  CAS  Google Scholar 

  7. Michot, J. M. et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Byun, D. J., Wolchok, J. D., Rosenberg, L. M. & Girotra, M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13, 195–207 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Akkaya, M. & Barclay, A. N. How do pathogens drive the evolution of paired receptors? Eur. J. Immunol. 43, 303–313 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Trowsdale, J. et al. The genomic context of natural killer receptor extended gene families. Immunol. Rev. 181, 20–38 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Barclay, A. N. & Hatherley, D. The counterbalance theory for evolution and function of paired receptors. Immunity 29, 675–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gaud, G., Lesourne, R. & Love, P. E. Regulatory mechanisms in T cell receptor signalling. Nat. Rev. Immunol. 18, 485–497 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Germain, R. N. & Stefanova, I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Pitcher, L. A. & van Oers, N. S. T-cell receptor signal transmission: who gives an ITAM? Trends Immunol. 24, 554–560 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vivier, E. & Daeron, M. Immunoreceptor tyrosine-based inhibition motifs. Immunol. Today 18, 286–291 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Gergely, J., Pecht, I. & Sarmay, G. Immunoreceptor tyrosine-based inhibition motif-bearing receptors regulate the immunoreceptor tyrosine-based activation motif-induced activation of immune competent cells. Immunol. Lett. 68, 3–15 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. An, H. et al. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat. Immunol. 9, 542–550 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Lowell, C. A. Src-family kinases: rheostats of immune cell signaling. Mol. Immunol. 41, 631–643 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Sasawatari, S. et al. The Ly49Q receptor plays a crucial role in neutrophil polarization and migration by regulating raft trafficking. Immunity 32, 200–213 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Gray-Owen, S. D. & Blumberg, R. S. CEACAM1: contact-dependent control of immunity. Nat. Rev. Immunol. 6, 433–446 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Ravetch, J. V. & Lanier, L. L. Immune inhibitory receptors. Science 290, 84–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Maasho, K. et al. The inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1) is expressed at high levels by human naive T cells and inhibits TCR mediated activation. Mol. Immunol. 42, 1521–1530 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Rowshanravan, B., Halliday, N. & Sansom, D. M. CTLA-4: a moving target in immunotherapy. Blood 131, 58–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Tang, A. L. et al. CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis. J. Immunol. 181, 1806–1813 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Barclay, A. N. & Van den Berg, T. K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu. Rev. Immunol. 32, 25–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Arias, C. F., Herrero, M. A., Cuesta, J. A., Acosta, F. J. & Fernandez-Arias, C. The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance. R. Soc. Open Sci. 2, 150016 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Hebell, T., Ahearn, J. M. & Fearon, D. T. Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 254, 102–105 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Orr, M. T. & Lanier, L. L. Natural killer cell education and tolerance. Cell 142, 847–856 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity? Nat. Rev. Immunol. 13, 764–769 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Grossman, Z. & Paul, W. E. Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses. Proc. Natl Acad. Sci. USA 89, 10365–10369 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sontag, E. D. A dynamic model of immune responses to antigen presentation predicts different regions of tumor or pathogen elimination. Cell Syst. 4, 231–241.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ke, Y., Sun, D., Jiang, G., Kaplan, H. J. & Shao, H. PD-L1(hi) retinal pigment epithelium (RPE) cells elicited by inflammatory cytokines induce regulatory activity in uveitogenic T cells. J. Leukoc. Biol. 88, 1241–1249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bertoli, C., Skotheim, J. M. & de Bruin, R. A. Control of cell cycle transcription during G1 and S phases. Nat. Rev. Mol. Cell Biol. 14, 518–528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bates, E. E. et al. APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif. J. Immunol. 163, 1973–1983 (1999).

    CAS  PubMed  Google Scholar 

  37. Zenarruzabeitia, O., Vitalle, J., Eguizabal, C., Simhadri, V. R. & Borrego, F. The biology and disease relevance of CD300a, an inhibitory receptor for phosphatidylserine and phosphatidylethanolamine. J. Immunol. 194, 5053–5060 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Pende, D. et al. Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction. Blood 107, 2030–2036 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Shamir, M., Bar-On, Y., Phillips, R. & Milo, R. SnapShot: timescales in cell biology. Cell 164, 1302–1302.e1 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Kaldor, N. A classificatory note on the determinateness of equilibrium. Rev. Econ. Stud. 1, 122–136 (1934).

    Article  Google Scholar 

  41. Linsley, P. S. et al. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 4, 535–543 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Becskei, A. & Serrano, L. Engineering stability in gene networks by autoregulation. Nature 405, 590–593 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Rosenfeld, N., Elowitz, M. B. & Alon, U. Negative autoregulation speeds the response times of transcription networks. J. Mol. Biol. 323, 785–793 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Garcia-Diaz, A. et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 19, 1189–1201 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Levi-Schaffer, F. & Mandelboim, O. Inhibitory and coactivating receptors recognising the same ligand: immune homeostasis exploited by pathogens and tumours. Trends Immunol. 39, 112–122 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Thompson, C. B. & Allison, J. P. The emerging role of CTLA-4 as an immune attenuator. Immunity 7, 445–450 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Walker, L. S. & Sansom, D. M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 11, 852–863 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Darvin, P., Toor, S. M., Sasidharan Nair, V. & Elkord, E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp. Mol. Med. 50, 165 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  49. Ahn, E. et al. Role of PD-1 during effector CD8 T cell differentiation. Proc. Natl Acad. Sci. USA 115, 4749–4754 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Smith, K. G. & Clatworthy, M. R. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat. Rev. Immunol. 10, 328–343 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to R. de Boer and M. Meizlish for useful comments on the manuscript. L.M. and M.R. are supported by the Netherlands Organization for Scientific Research (NWO Vici 918.15.608). R.M. is supported by the Howard Hughes Medical Institute and a grant from the US National Institutes of Health (1R01 AI144152-01).

Author information

Authors and Affiliations

  1. Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands

    Matevž Rumpret, Julia Drylewicz, Laura J. E. Ackermans, José A. M. Borghans & Linde Meyaard

  2. Oncode Institute, Utrecht, Netherlands

    Matevž Rumpret & Linde Meyaard

  3. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Ruslan Medzhitov

  4. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

    Ruslan Medzhitov

Authors
  1. Matevž Rumpret
    View author publications

    Search author on:PubMed Google Scholar

  2. Julia Drylewicz
    View author publications

    Search author on:PubMed Google Scholar

  3. Laura J. E. Ackermans
    View author publications

    Search author on:PubMed Google Scholar

  4. José A. M. Borghans
    View author publications

    Search author on:PubMed Google Scholar

  5. Ruslan Medzhitov
    View author publications

    Search author on:PubMed Google Scholar

  6. Linde Meyaard
    View author publications

    Search author on:PubMed Google Scholar

Contributions

L.M., R.M. and J.A.M.B. conceptualized the idea; J.D. and L.J.E.A. performed the mathematical modelling; M.R. performed the literature study and wrote the original draft; M.R., J.D., J.A.M.B., R.M. and L.M. discussed, reviewed and edited the manuscript.

Corresponding author

Correspondence to Linde Meyaard.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thanks G. Freeman, L. Martinet, T. Pradeu, E. Vivier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rumpret, M., Drylewicz, J., Ackermans, L.J.E. et al. Functional categories of immune inhibitory receptors. Nat Rev Immunol 20, 771–780 (2020). https://doi.org/10.1038/s41577-020-0352-z

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41577-020-0352-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing