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Complement component C1q is an immunological rheostat that regulates Fc:Fc\(\gamma\)R interactions

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Abstract

Though binding sites for the complement factor C1q and the canonical fragment crystallizable (Fc) gamma receptors (Fc\(\gamma\)Rs) on immunoglobulin G (IgG) molecules overlap, how C1q decoration of immune complexes (ICs) influences their ability to engage Fc\(\gamma\)Rs remains unknown. In this report, we use recombinant human Fc multimers as stable IC mimics to show that C1q engagement of ICs directly and transiently inhibits their interactions with Fc\(\gamma\)RIII (CD16) on human natural killer (NK) cells. This inhibition occurs by C1q engagement alone as well as in concert with other serum factors. Furthermore, the inhibition of Fc\(\gamma\)RIII engagement mediated by avid binding of C1q to ICs is directly associated with IC size and dependent on the concentrations of both C1q and Fc multimers present. Functionally, C1q-mediated Fc blockade limits the ability of NK cells to induce the upregulation of the cosignaling molecule, 4-1BB (CD137), and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Although C1q is traditionally viewed as a soluble effector molecule, we demonstrate that C1q may also take on the role of an “immunologic rheostat,” buffering Fc\(\gamma\)R-mediated activation of immune cells by circulating ICs. These data define a novel role for C1q as a regulator of immune homeostasis and add to our growing understanding that complement factors mediate pleiotropic effects.

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Data Availability

The data described in this manuscript is available upon request with the corresponding author.

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Acknowledgements

E.C.S. is a Ph.D. candidate at the University of Maryland, School of Medicine. This work is submitted in partial fulfillment of the requirement for the Ph.D. We would like to thank Dr. Elizabeth Fitzpatrick and Dr. Jane Owens for reviewing the manuscript. We would like to also thank Gliknik, Inc. for providing the GL-2045, G001, and G019 reagents.

Funding

This research was funded by the Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland SOM. GL-2045, G001, and G019 were provided, free of charge, by Gliknik, Inc.

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Author notes

  1. Xiaoyu Zhang and Scott E. Strome are co-last authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    Edward C. So, Hua Zhou, Ariana Greenwell, Erin E. Burch, Yaping Ji & Xiaoyu Zhang

  2. Gliknik Inc., Baltimore, MD, USA

    Emmanuel Y. Mérigeon, Henrik S. Olsen & David S. Block

  3. Department of Epidemiology and Public Health, Division of Biostatistics and Bioinformatics, University of Maryland School of Medicine, Baltimore, MD, USA

    Søren M. Bentzen

  4. Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center (UTHSC), 910 Madison Avenue, 10th floor Suite 1002, Memphis, TN, 38163, USA

    Scott E. Strome

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  1. Edward C. So
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Contributions

All authors made substantive intellectual contributions to the experimental design; E.C.S. and H.Z. performed the majority of the studies; E.C.S., H.Z., H.S.O., D.S.B., X.Z., and S.E.S. analyzed data and interpreted the studies; S.M.B. performed all statistical analyses; E.C.S., X.Z. and S.E.S. designed research; E.C.S., X.Z. and S.E.S. original draft preparation; E.C.S., H.S.O., D.S.B., X.Z., and S.E.S. review and editing; X.Z. and S.E.S. supervised the project; and all authors had input into the final version of the manuscript.

Corresponding author

Correspondence to Scott E. Strome.

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Conflict of interest disclosure

Dr. Scott E. Strome is a Cofounder, stockholder, and paid consultant for Gliknik Inc., a biotechnology company. He also serves on the SAB and holds stock options for Virion Inc. Finally, he receives significant royalties from the Mayo Clinic, for licensed IP surrounding the manipulation of the PD-1:PD-L1 pathway for the treatment of cancer.

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Supplemental Figure 1.

 A plate-based assay demonstrating the binding properties of GL-2045 or G019 (various concentrations) to immobilized C1q.

Supplemental Figure 2. A Assessment of C1q receptor expression on NK cells.Isolated NK cells were stained with various antibodies specific for different C1q receptors (LAIR1, LAIR2, cC1qR, gC1qR, and CR1) and the expression was determined by flow cytometry. B Various concentrations of human C1q (0, 5, 20, and 100 µg/ml) were cultured with human NK cells in order to assess C1q binding. An anti-C1q antibody was used to evaluate the levels of C1q binding by FACS. 

Supplemental Figure 3. A Isolated NK cells were incubated with culture media only, mIgG1 (10 µg/ml), or anti-CD16 (10 µg/ml) prior to the addition of DyLight 488 labeled G019 (1 µg/ml). Binding of G019 to NK cells was determined by flow cytometry. Data are shown from a representative sample (top panel) and summarized MFI (mean ± SEM) from three experiments (bottom panel). B FcγRIIA- or FcγRIIB-expressing CHO cells were incubated with Dylight 488 labeled GL-2045 in the presence or absence of recombinant human C1q (100 µg/ml). Binding of GL-2045 to CHO cell lines was determined by flow cytometry. Data are shown from a representative experiment (left panels) and as the summarized MFI (mean ± SEM) from three experiments (right panels). *p < 0.05, **p < 0.01. (PPTX 224 KB)

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So, E.C., Zhou, H., Greenwell, A. et al. Complement component C1q is an immunological rheostat that regulates Fc:Fc\(\gamma\)R interactions. Immunogenetics 75, 369–383 (2023). https://doi.org/10.1007/s00251-023-01311-x

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