The Fcγ-binding glycoprotein gp34 of Human cytomegalovirus targets IgG switched memory B cells to mediate humoral immune evasion

Abstract: Recurrent exposure to pathogens triggers high affinity antibody responses predominantly driven by IgG+ memory B cells. Human cytomegalovirus (HCMV), however, replicates and disseminates even in the presence of HCMV-specific neutralizing IgG antibodies. One factor that has been linked to this phenomenon is the HCMV glycoprotein gp34 encoded by the RL11 gene. gp34 binds IgG-Fc and antagonizes IgG-mediated activation of immune cells via IgG-Fc recognizing Fc-gamma receptors (FcγRs). Viral IgG-Fc binding molecules like gp34 (vFcγRs) have been shown to protect HCMV infected cells from potent IgG-mediated antiviral effector mechanisms such as antibody-dependent cellular cytoxicity (ADCC). As vFcγRs up until now were described as type I transmembrane proteins, their function has been studied solely with regard to the interaction between effector cell and infected cells.
Here, we show that the gp34 ectodomain is released during active phases of HCMV infection and introduced into the human circulation (soluble gp34). We found that soluble gp34 binds specifically to the IgG B cell receptor (BCR), inducing internalization of the BCR and upregulation of co-stimulatory molecules in a tyrosine kinase Syk-independent manner. GP34 activates the mTORC1 signaling axis responsible for protein synthesis and cell proliferation. However, this activation is short-lived and ineffective in sustaining B cell expansion, plasmablast formation and immunoglobulin production, rendering gp34-activated B cells anergic eventually leading to cell death. This novel mechanism of host manipulation is unique among the so far studied pathogen-Fc binding factors such as Proteins A of Staphylococcus aureus.
Additionally, gp34 triggers the secretion of the pro-inflammatory cytokine- TNF-alpha by IgG+ B cells thereby regulating the activation of non-IgG+ B cells. These findings show that HCMV targets the activation and maturation of switched memory B cells potentially impairing secondary immune responses and suggest HCMV to be a factor that can dampen recall immune responses in infected individuals

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Anmerkungen: Universität Freiburg, Dissertation, 2021

Klassifikation und Themen

• Schlagwort: B-Lymphozyt ; Immunglobulin G ; Cytomegalie-Virus ; B-Zelle ; Antikörper

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2021
• Urheber: Cramer, Precious
• Beteiligte Personen und Organisationen: Hengel, Hartmut ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Weitere Informationen

• DOI: 10.6094/UNIFR/221477
• URN: urn:nbn:de:bsz:25-freidok-2214775
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:52 MEZ