title: TRIM21 Immune Signaling Is More Sensitive to Antibody Affinity Than Its Neutralization Activity.
abstract: Ab-coated viruses can be detected in the cytosol by the FcR tripartite motif-containing 21 (TRIM21), which rapidly recruits the proteasomal machinery and triggers induction of immune signaling. As such, TRIM21 plays a key role in intracellular protection by targeting invading viruses for destruction and alerting the immune system. A hallmark of immunity is elicitation of a balanced response that is proportionate to the threat, to avoid unnecessary inflammation. In this article, we show how Ab affinity modulates TRIM21 immune function. We constructed a humanized monoclonal IgG1 against human adenovirus type 5 (AdV5) and a panel of Fc-engineered variants with a wide range of affinities for TRIM21. We found that IgG1-coated viral particles were neutralized via TRIM21, even when affinity was reduced by as much as 100-fold. In contrast, induction of NF-κB signaling was more sensitive to reduced affinity between TRIM21 and the Ab variants. Thus, TRIM21 mediates neutralization under suboptimal conditions, whereas induction of immune signaling is balanced according to the functional affinity for the incoming immune stimuli. Our findings have implications for engineering of antiviral IgG therapeutics with tailored effector functions.
authors.affiliation: Centre for Immune Regulation, Department of Biosciences, University of Oslo, N-0371 Oslo, Norway.|Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Foss
authors.affiliation: Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2-0QH, United Kingdom.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Watkinson
authors.affiliation: Centre for Immune Regulation, Department of Biosciences, University of Oslo, N-0371 Oslo, Norway.|Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Algirdas
authors.initials: A
authors.lastname: Grevys
authors.affiliation: Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Martin B
authors.initials: MB
authors.lastname: McAdam
authors.affiliation: Centre for Immune Regulation, Department of Biosciences, University of Oslo, N-0371 Oslo, Norway.|Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Malin
authors.initials: M
authors.lastname: Bern
authors.affiliation: Centre for Immune Regulation, Department of Biosciences, University of Oslo, N-0371 Oslo, Norway.|Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Lene Stokken
authors.initials: LS
authors.lastname: Høydahl
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo N-0424, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.affiliation: Department of Bacteriology and Immunology, Norwegian Institute of Public Health, N-0403 Oslo, Norway.|Department of Chemical Pharmacy, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
authors.forename: Terje E
authors.initials: TE
authors.lastname: Michaelsen
authors.affiliation: Centre for Immune Regulation, Department of Biosciences, University of Oslo, N-0371 Oslo, Norway.|Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.affiliation: Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2-0QH, United Kingdom.
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
authors.affiliation: Centre for Immune Regulation, Department of Biosciences, University of Oslo, N-0371 Oslo, Norway.|Centre for Immune Regulation, Department of Immunology, Oslo University Hospital Rikshospitalet, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
mesh_terms: D000260:Adenoviruses, Human / Q000276:immunology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D009500:Neutralization Tests; D012261:Ribonucleoproteins / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D020349:Surface Plasmon Resonance; D000099207:SS-A Antigen
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D007074:Immunoglobulin G; D016328:NF-kappa B; D012261:Ribonucleoproteins; D000099207:SS-A Antigen