Polarization of Vδ2 T cells to a Th2-like phenotype promotes plasmablast differentiation and possesses pro-fibrotic properties in IgG4-related disease

• Published in: Frontiers in immunology Vol. 16; p. 1550405
• Main Authors: Li, Jieqiong, Wang, Mu, Zhou, Jiaxin, Fei, Yunyun, Li, Mengtao, Zhao, Yan, Zeng, Xiaofeng, Peng, Linyi, Zhang, Wen
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 27.03.2025
• Subjects: Aged; Cell Differentiation - immunology; Cytokines - metabolism; Female; Fibrosis; GATA3 Transcription Factor - metabolism; Humans; IgG4-related disease; IL-21–STAT3; Immunoglobulin G4-Related Disease - immunology; Immunoglobulin G4-Related Disease - metabolism; Immunoglobulin G4-Related Disease - pathology; Immunology; Interleukin-21; Interleukins - metabolism; Lymphocyte Activation; Male; Middle Aged; Phenotype; Plasma Cells - immunology; Plasma Cells - metabolism; plasmablasts; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism; Th2-like phenotype; Vδ2 T cells; Th2-like phenotype; plasmablasts; IgG4-related disease; IL-21–STAT3; Vδ2 T cells
• DOI: 10.3389/fimmu.2025.1550405
• ISSN: 1664-3224

To explore the phenotype and role of gamma delta (γδ) T cells in the pathogenesis of IgG4-related disease (IgG4-RD). Flow cytometry and quantitative RT-PCR were employed to analyze γδ T cell subsets, chemokine receptor expression, cytokine production, pro-fibrotic gene expression, and transcription factor profiles. Immunofluorescence assessed Vδ2 T cell infiltration in affected tissues. Chemotaxis assays and co-culture experiments investigated Vδ2 T cell migration and their influence on B cell differentiation. The impact of IL-21 stimulation and JAK/STAT3 inhibitors on γδ T cell was also evaluated. Patients with IgG4-RD exhibited decreased peripheral Vδ2 T cells displaying a Th2-like phenotype characterized by elevated Th2 cytokine production and activated IL-21-STAT3-Blimp-1-GATA3 pathway. Vδ2 T cells accumulated in affected tissues through CCR7 upregulation, and co-localizing with B cells. Both Vδ2 T cells and culture supernatants from IgG4-RD patients promoted B cell differentiation. IL-21 stimulation augmented pSTAT3, Blimp-1, and GATA3 expression in Vδ2 T cells, while JAK and STAT3 inhibitors attenuated these effects. IgG4-RD patients exhibited increased TGF-β and pro-fibrotic gene expression in γδ T cells. Within the IL-21-rich microenvironment of IgG4-RD, peripheral Vδ2 T cells acquire a Th2-like phenotype via the IL-21-STAT3-Blimp-1-GATA3 pathway. Targeting JAK/STAT3 inhibitors holds therapeutic potential for IgG4-RD.