Patrolling Monocytes Mediate Virus Neutralizing IgG Effector Functions: Beyond Neutralization Capacity

Abdelrahman Elwy^1,2*Swati Dhiman²Hossam Abdelrahman²Julia Specht²Theresa-Charlotte Christ²Julia Falkenstein³Harpreet Kaur²Lisa Holnsteiner²Judith Lang²Matthias Mack⁴Falk Nimmerjahn⁵Wiebke Hansen³Karl Lang²

• ¹Institut für Immunologie, Universitätsklinikum Essen, Essen, North Rhine-Westphalia, Germany
• ²Institute of Immunology, Medical Faculty, University of Duisburg-Essen,, Essen, Germany
• ³Institute for Medical Microbiology, University Hospital Essen, Essen, North Rhine-Westphalia, Germany
• ⁴Department of Nephrology, University Hospital Regensburg,, Regensburg, Germany
• ⁵Division of Genetics, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Bavaria, Germany

Neutralizing antibodies (nAbs) are pivotal in developing fast, broadly protective therapeutics against novel pandemic viruses. Despite their well-known direct neutralization capacity, their effector mechanisms via Fc receptors remain poorly understood. Identifying the types of effector cells engaged in antibody-mediated effector functions is essential for regulating their activities. Using the lymphocytic choriomeningitis virus (LCMV), we show that nAbs obtained from immune sera or monoclonal LCMV-specific nAbs show dependency on Fc receptors. We demonstrate that therapy with nAbs is highly protective in the presence of patrolling monocytes.These monocytes bind nAbs primarily via FcγRIV, targeting virus-infected cells, and thereby limiting virus propagation. Depleting patrolling monocytes or blocking FcγRIV resulted in a substantial loss of virus control by nAbs, indicating the pivotal role of patrolling monocytes in the antiviral activity of these antibodies. In conclusion, our findings highlight that, alongside direct neutralization, nAbs primarily exert their effects through the involvement of patrolling monocytes.