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. 2025 Aug;175(4):434-443.
doi: 10.1111/imm.13940. Epub 2025 May 4.

Non-Antigen-Specific B Cells Induced Regulatory CD4+ T Cells Through Decreasing T Cell Activation

Chien-Hui Chien  1 , Tsai-Ying Yeh  2 , Bor-Luen Chiang  3   4
Affiliations

Non-Antigen-Specific B Cells Induced Regulatory CD4+ T Cells Through Decreasing T Cell Activation

Chien-Hui Chien et al. Immunology. 2025 Aug.

Abstract

Our previous findings demonstrated that naïve B cells elicit suppressive CD4+ regulatory T (Treg) cells, named as Treg-of-B cells. However, the capability of antigen-specific B cells in that process remains unclear. Using ovalbumin (OVA) as a model antigen, the present study showed that B cells from OVA-immunised mice decreased that ability. Instead, OVA-activated OVA-specific (OB1) B cells induced effector-like T-of-OB1 cells without regulatory function. Phenotypically, Treg-of-B cells reduced the production of interferon (IFN)-γ, interleukin (IL)-17 and IL-2 and expressed CD62L, PD1 and endothelial cell adhesion molecule 1 (PECAM1). Functionally, adoptive transfer of Treg-of-B cells significantly attenuated Th1 cell-mediated delayed-type hypersensitivity (DTH) responses and inhibited IFN-γ-producing Th1 cells, while T-of-OB1 cells did not. Mechanistically, activated antigen-specific B cells increased the expression of costimulatory molecules and promoted higher T cell activation, contributing to effector T cell phenotype. Conversely, Treg-of-B cells exhibited lower T cell activation, possibly mediated through the expression of PECAM1, Dusp2, Dusp5, Ptpn7, Ptpn22 and Ms4a4b. These findings suggest that non-antigen-specific B cells elicit CD4+ Treg cells, potentially via attenuating T cell activation, whereas that capacity is absent in antigen-specific B cells. This distinction underscores the critical role of B cell antigen specificity in immune regulation and inflammation.

Keywords: T cell activation; antigen specificity; costimulatory molecules; interferon (IFN)‐γ; regulatory T (Treg) cells; suppressive function.

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