SARS-CoV-2-Induced IgG Repertoires Shape Gamma-Delta T Cell Responses: Evidence for Direct IgG-Membrane Interaction According to Disease Severity

Immunoglobulin G (IgG) is a central component of humoral immunity in coronavirus disease 2019 (COVID-19); however, increasing evidence suggests that infection-induced IgG repertoires exert immunomodulatory effects beyond classical antiviral functions. In this study, we investigated whether IgG from patients with moderate or severe COVID-19 directly modulates human peripheral γδ T cells and whether these effects are associated with disease severity-dependent IgG idiotype profiles. Purified IgG from non-exposed healthy controls, moderate COVID-19 patients, or severe COVID-19 patients was incubat-ed with peripheral blood mononuclear cells from healthy donors. γδ T cell phenotype, subset distribution, homing markers, and cytokine production were assessed by flow cytometry, while direct IgG-cell interactions were evaluated using fluorescent IgG binding assays. In parallel, proteomic profiling using human proteome microarrays was performed to identify γδ T cell-expressed protein targets recognized by COVID-19-induced IgG. IgG from SARS-CoV-2-infected individuals selectively reduced Vγ9⁺Vδ2⁺ γδ T cells, altered memory differentiation, downregulated CCR5, CCR6, and CD161 expression, and reshaped cytokine production in a severity-dependent manner. COVID-19 IgG bound directly to the γδ T cell membrane without inducing apoptosis, indicating a non-cytotoxic mechanism of modulation. Proteomic analysis revealed a marked expansion and diversification of γδ T cell-associated IgG targets in COVID-19, particularly in severe disease, with enrichment of pathways related to immune signaling and inflammation. Collectively, these findings identify γδ T cells as direct functional targets of SARS-CoV-2-induced IgG repertoires and demonstrate that disease severity shapes IgG idiotype networks with distinct immunomodulatory capacities. This work highlights a previously underappreciated antibody-mediated mechanism contributing to immune dysregulation in COVID-19.