TGF-beta promotes human T follicular helper cell stemness properties at the expense of effector function

Transforming growth factor-β (TGF-β) is a multifunctional cytokine implicated in immune regulation, T-cell differentiation, and the maintenance of cellular stemness. Prior studies have shown that TGF-β promotes stemness across a wide range of cell types and facilitates the differentiation of naïve CD4⁺ T cells into various T helper cell subsets.

However, its precise effects on TFH effector function and stem-like properties remain poorly understood. Here, the dual regulatory roles of TGF-β1 in modulating TFH effector functions and stem-like properties were investigated. We found that TGF-β1 treatment in vitro promoted human naïve CD4+ T cells differentiation into CXCR3⁺ TFH, but significantly attenuated their effector molecule expression and TFH-mediated memory B-cell differentiation and antibody production, whereas it enhanced the expression of stemness-associated molecules in TFH cells both differentiated in vitro from naïve CD4+ T cells and isolated from blood.