Precious Cramer, Stefan F H Neys, Manuela Fiedler, Raquel Lorenzetti, Henrike Reinhard, Iga Janowska, Julian Staniek, Ann-Katrin Kohl, Petra Hadlová, Magdalena Huber, Bodo Plachter, Clarissa Read, Valeria Falcone, Jens von Einem, Katja Hoffmann, Tihana Lenac Rovis, Stipan Jonjić, Philipp Kolb, Marta Rizzi, Hartmut Hengel
Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV Fcγ-binding glycoprotein 34 modulates humoral immunity by binding to IgG⁺ memory B cells. gp34-B cell receptor (BCR) interaction initiates activation of the PDK1/AKT/mTOR/S6 pathway and BCR internalization in a SYK-independent manner. Prolonged stimulation also induces B-cell activation via upregulation of CD69 and CD86. In a T-cell-dependent response, however, interaction with gp34 blocks B-cell proliferation, differentiation into plasmablasts, and soluble IgG production, while stimulating TNF-α secretion. Through gp34 stimulation on IgG⁺ B cells, neighboring IgM⁺ and IgA⁺ B cells are likewise impaired in proliferation, plasmablast formation, and immunoglobulin secretion. In summary, gp34 specifically interacts with IgG⁺ memory B cells, inducing a hyporesponsive state across the B-cell compartment through direct and indirect regulation. This reveals a novel mode of viral evasion from B-cell responses by suppressing secondary immunity.