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J Immunol ; 205(12): 3456-3467, 2020 12 15.
Article de Anglais | MEDLINE | ID: mdl-33188070

RÉSUMÉ

Abs of the IgG isotype mediate effector functions like Ab-dependent cellular cytotoxicity and Ab-dependent cellular phagocytosis by Fc interactions with FcγRs and complement-dependent cytotoxicity upon IgG-Fc binding to C1q. In this study, we describe the crucial role of the highly conserved dual glycines at position 236-237 in the lower hinge region of human IgG, including the lack of one glycine as found in IgG2. We found several permutations in this region that either silence or largely abrogate FcγR binding and downstream FcγR effector functions, as demonstrated by surface plasmon resonance, Ab-dependent cellular phagocytosis, and Ab-dependent cellular cytotoxicity assays. Although the binding regions of FcγRs and C1q on the IgG-Fc largely overlap, IgG1 with a deletion of G236 only silences FcγR-mediated effector functions without affecting C1q-binding or activation. Several mutations resulted in only residual FcγRI binding with differing affinities that are either complement competent or silenced. Interestingly, we also found that IgG2, naturally only binding FcγRIIa, gains binding to FcγRI and FcγRIIIa after insertion of G236, highlighting the crucial importance of G236 in IgG for FcγR interaction. These mutants may become invaluable tools for FcγR-related research as well as for therapeutic purposes in which only complement-mediated functions are required without the involvement of FcγR.


Sujet(s)
Séquence d'acides aminés , Activation du complément , Complément C1q , Immunoglobuline G , Récepteurs du fragment Fc des IgG , Délétion de séquence , Résonance plasmonique de surface , Complément C1q/composition chimique , Complément C1q/génétique , Complément C1q/immunologie , Glycine/composition chimique , Glycine/génétique , Glycine/immunologie , Cellules HEK293 , Humains , Immunoglobuline G/composition chimique , Immunoglobuline G/génétique , Immunoglobuline G/immunologie , Récepteurs du fragment Fc des IgG/composition chimique , Récepteurs du fragment Fc des IgG/génétique , Récepteurs du fragment Fc des IgG/immunologie
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