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New insights into the immune functions of complement

Nature Reviews Immunology volume 19, pages 503–516 (2019)Cite this article

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Abstract

The recognition of microbial or danger-associated molecular patterns by complement proteins initiates a cascade of events that culminates in the activation of surface complement receptors on immune cells. Such signalling pathways converge with those activated downstream of pattern recognition receptors to determine the type and magnitude of the immune response. Intensive investigation in the field has uncovered novel pathways that link complement-mediated signalling with homeostatic and pathological T cell responses. More recently, the observation that complement proteins also act in the intracellular space to shape T cell fates has added a new layer of complexity. Here, we consider fundamental mechanisms and novel concepts at the interface of complement biology and immunity and discuss how these affect the maintenance of homeostasis and the development of human pathology.

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Fig. 1: Intracellular interactions and fates of microorganisms opsonized with C3 in the extracellular milieu.
Fig. 2: Synergistic interactions between complement and Toll-like receptors.
Fig. 3: Complement-mediated T cell activation.

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Acknowledgements

The authors thank D. McClellan for editorial assistance. J.D.L. also thanks R. Weaver and S. Weaver for the generous endowment of his professorship. Given the broad scope of this Review, the authors often refer to specialized review articles rather than primary literature, and they have been able to include only selected examples of the breadth of the transformative work in the field; they therefore want to thank all their colleagues who are not specifically cited for their contributions and their understanding. This work was supported by grants from the US National Institutes of Health (AI068730, AI030040, DE024153 and DE024716).

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Nature Reviews Immunology thanks V. Holers and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Edimara S. Reis & John D. Lambris

  2. National Center for Scientific Research ‘Demokritos’, Athens, Greece

    Dimitrios C. Mastellos

  3. Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    George Hajishengallis

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All authors researched the literature, contributed to discussions of the content, wrote the text and edited the manuscript before submission.

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Correspondence to John D. Lambris.

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Competing interests

J.D.L. and G.H. are inventors on patents or patent applications that describe the use of complement inhibitors for therapeutic purposes. J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation Compstatin analogues such as AMY-101), and the inventor of the Compstatin technology licensed to Apellis Pharmaceuticals (that is, 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives). E.S.R. and D.C.M. declare no competing interests.

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Reis, E.S., Mastellos, D.C., Hajishengallis, G. et al. New insights into the immune functions of complement. Nat Rev Immunol 19, 503–516 (2019). https://doi.org/10.1038/s41577-019-0168-x

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