C1q-mediated steric hindrance limits FcγR contribution to antibody-driven phagocytosis by human neutrophils

Abstract

Phagocytosis and killing of bacteria by neutrophils is a key driver of human immunity against invading infections. IgG antibodies targeting the bacterial surface can potently enhance phagocytic uptake by engaging Fc gamma receptors (Fc{gamma}Rs) on the neutrophil membrane. In addition, IgG-mediated complement activation triggers surface deposition of complement opsonins that engage complement receptors (CRs) to further enhance target cell clearance. In this paper, we reveal that complement deposition prevents engagement of Fc{gamma}Rs to the Fc-domain of surface-bound IgG molecules. When complement is present, we observe that blockade of Fc{gamma}Rs does not influence phagocytosis of both Gram-positive and -negative bacteria (using Staphylococcus aureus and Klebsiella pneumoniae as model organisms). Complement-mediated hindrance of Fc{gamma}R engagement was observed in different model conditions, for example using either pre-existing polyclonal antibodies in human serum or recombinant monoclonal antibodies (mAbs) targeting different bacterial antigens. Using Fc engineering, we found that inhibition of Fc{gamma}R binding is dependent on the ability of IgGs to form IgG hexamers. Mechanistically, we show that complement proteins, in particular C1q, directly prevents the interaction between IgG-Fc and Fc{gamma}R by steric hindrance. Together, these insights help us define the respective roles of Fc{gamma}R and CR in neutrophil phagocytosis, while also providing important fundamental insights for therapeutic antibody development.

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BibTeX RIS

BibTeX

@misc{gronloh2026c1qmediated,
  title = {{C1q-mediated steric hindrance limits FcγR contribution to antibody-driven phagocytosis by human neutrophils}},
  author = {M. L. B. Grönloh and L. de Vor and S. A. Zwarthoff and J. Venema and R. Smits and S. Baijens and M. Ruyken and P. Aerts and C. J. C. de Haas and K. P. M. van Kessel and L. Trouw and B. W. Bardoel and S. H. M. Rooijakkers},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.30.755584},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755584v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - C1q-mediated steric hindrance limits FcγR contribution to antibody-driven phagocytosis by human neutrophils
AU  - M. L. B. Grönloh
AU  - L. de Vor
AU  - S. A. Zwarthoff
AU  - J. Venema
AU  - R. Smits
AU  - S. Baijens
AU  - M. Ruyken
AU  - P. Aerts
AU  - C. J. C. de Haas
AU  - K. P. M. van Kessel
AU  - L. Trouw
AU  - B. W. Bardoel
AU  - S. H. M. Rooijakkers
PY  - 2026
DA  - 2026/09/30
PB  - bioRxiv
DO  - 10.64898/2026.09.30.755584
UR  - https://www.biorxiv.org/content/10.64898/2026.09.30.755584v1
AB  - Phagocytosis and killing of bacteria by neutrophils is a key driver of human immunity against invading infections. IgG antibodies targeting the bacterial surface can potently enhance phagocytic uptake by engaging Fc gamma receptors (Fc{gamma}Rs) on the neutrophil membrane. In addition, IgG-mediated complement activation triggers surface deposition of complement opsonins that engage complement receptors (CRs) to further enhance target cell clearance. In this paper, we reveal that complement deposition prevents engagement of Fc{gamma}Rs to the Fc-domain of surface-bound IgG molecules. When complement is present, we observe that blockade of Fc{gamma}Rs does not influence phagocytosis of both Gram-positive and -negative bacteria (using Staphylococcus aureus and Klebsiella pneumoniae as model organisms). Complement-mediated hindrance of Fc{gamma}R engagement was observed in different model conditions, for example using either pre-existing polyclonal antibodies in human serum or recombinant monoclonal antibodies (mAbs) targeting different bacterial antigens. Using Fc engineering, we found that inhibition of Fc{gamma}R binding is dependent on the ability of IgGs to form IgG hexamers. Mechanistically, we show that complement proteins, in particular C1q, directly prevents the interaction between IgG-Fc and Fc{gamma}R by steric hindrance. Together, these insights help us define the respective roles of Fc{gamma}R and CR in neutrophil phagocytosis, while also providing important fundamental insights for therapeutic antibody development.
ER  -

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