Background/Purpose: To explore the phenotype and role of gamma delta (γδ) T cells in the pathogenesis of IgG4-related disease (IgG4-RD), focusing on the effect on plasmablasts differentiation and immunoglobulin production.

Methods: Peripheral γδ T cells, chemokine receptor expression, intracellular cytokines expression, and transcription factors expression were quantified by flow cytometry and qRT-PCR. The infiltration of Vδ2 T cells, and locations of B cells and chemokine receptors within the tissue involved were examined by immunofluorescence. Transwell assay was used to detect the chemotactic rate of Vδ2 T cell to specific chemokine. CD19+ B cells were cultivated with the expanded Vδ2 T cells or Vδ2 T-SNs. B cell subsets and immunoglobulin production were assessed by flow cytometry and ELISA. The effects of IL-21, JAK inhibitor, and STAT3 inhibitor on Vδ2 T cells were determined by flow cytometry.

Results: Proportions of γδ T cells, especially Vδ2 T cells were significantly decreased in the peripheral blood of patients with active IgG4-RD. Vδ2 T cells from IgG4-RD produced high levels of Th2-type cytokines (IL-4, IL-5, IL-9, IL-13), IL-21R, GATA3, Blimp-1, and CCR7. But the expressions of Th1-type cytokines, CXCR5, ICOS, CD40L, and transcription factor TBX21, FOXP3, RORC, and BCL6 were similar with or not higher than healthy controls (HCs). Immunofluorescent staining revealed the accumulation of Vδ2 T cells and co-localization of Vδ2 T cells, B cells, and CCR7/CCL21 in the involved submandibular gland tissues. The migration rate of IgG4-RD Vδ2 T cells to CCL21 was higher than that of HC. In vitro, both expanded Vδ2 T cells and supernatant (SN) from active IgG4-RD patients promoted B cell differentiation into plasmablasts and immunoglobulin production. The expressions of pSTAT3 (pY705), GATA3 and Blimp-1 in Vδ2 T cells were increased in patients with IgG4-RD compared to HCs, and GATA3 expression further increased after IL-4 stimulation. And there were positive correlations among the protein levels of pSTAT3, Blimp-1, and GATA3. IL-21 stimulation promoted the expressions of pSTAT3, Blimp-1, and GATA3 in Vδ2 T cells from HCs, while JAK inhibitors (Baricitinib and Tofacitinib) and STAT3 inhibitors (S3I-201) inhibited this process. In addition, TGF-β was increased in the patients with IgG4-RD compared with HCs in the γδ T cells and its subsets, and the pro-fibrotic genes expression also increased in γδ T cells from IgG4-RD patients, including ACTA2, COL1A1, COL1A2, and COL3A1.

Conclusion: Peripheral Vδ2 T cells obtain a Th2-like phenotype in the IL-21 highexpressed microenvironment of IgG4-RD through the IL-21—STAT3—Blimp-1—GATA3 pathway, and play a role in promoting plasmablasts differentiation and immunoglobulin production. The high expression of CCR7 may contribute to its chemotaxis to the involved tissues and the interaction with B cells. JAKi and STAT3i, as well as IL-21i inhibit the Th2-like phenotypes in Vδ2 T cells mediated by IL-21-pSTAT3 pathway, thereby opening up new therapeutic approaches in IgG4-RD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-21-stat3-pathway-mediated-th2-like-v%ce%b42-t-cells-promote-plasmablasts-differentiation-in-igg4-related-disease/