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

## TL;DR

This study shows that SARS-CoV-2 infection changes IgG antibodies, which in turn directly affect gamma-delta T cells, especially in severe cases of COVID-19.

## Contribution

The study reveals a new mechanism where IgG repertoires directly modulate gamma-delta T cells, depending on disease severity.

## Key findings

- IgG from SARS-CoV-2 patients alters gamma-delta T cell phenotype and cytokine responses.
- Severe disease is linked to expanded IgG networks targeting gamma-delta T cell proteins.
- IgG binds to gamma-delta T cells without causing cell death, suggesting a non-cytotoxic modulation.

## Abstract

What are the main findings?
SARS-CoV-2 infection generates IgG repertoires that directly interact with γδ T cells, reshaping their phenotype, homing profile, and cytokine responses in a disease severity-dependent manner.Severe COVID-19 is associated with expanded IgG idiotype networks that recognize γδ T cell-expressed proteins and map to inflammatory and immune-regulatory signaling pathways.

SARS-CoV-2 infection generates IgG repertoires that directly interact with γδ T cells, reshaping their phenotype, homing profile, and cytokine responses in a disease severity-dependent manner.

Severe COVID-19 is associated with expanded IgG idiotype networks that recognize γδ T cell-expressed proteins and map to inflammatory and immune-regulatory signaling pathways.

What are the implications of the main findings?
These data position γδ T cells as interpreters of antibody-encoded immune information, revealing a previously underappreciated layer of humoral–unconventional T cell crosstalk in COVID-19.Profiling IgG idiotype repertoires may open new conceptual avenues for understanding and modulating immune dysregulation in viral infections beyond antigen-centric paradigms.

These data position γδ T cells as interpreters of antibody-encoded immune information, revealing a previously underappreciated layer of humoral–unconventional T cell crosstalk in COVID-19.

Profiling IgG idiotype repertoires may open new conceptual avenues for understanding and modulating immune dysregulation in viral infections beyond antigen-centric paradigms.

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.