Th17 Cells Impair Epithelial Defense Against Intracellular Bacteria in Part Through TGF-β

While Th1 and Th17 cells are well known for their distinct roles in host defense, how these effector CD4⁺ T-cell subsets influence epithelial responses to intracellular bacteria remains unclear. Here, we investigated whether Th1 or Th17 cells modulate the intracellular survival of Escherichia coli 7.2 (Ec7.2), a clinical isolate from oral lichen planus (OLP) tissue, in oral keratinocytes. To assess antigen-specific and antigen-independent T-cell effects, we established a co-culture system using IFN-γ-pretreated, Ec7.2-infected immortalized murine oral keratinocytes (IMOK) and Th1 or Th17 cells differentiated from OT-II-restricted CD4⁺ T cells, in the absence or presence of cognate peptide. Th1 cells reduced intracellular Ec7.2 in an antigen-dependent manner, whereas Th17 cells consistently increased bacterial persistence through largely antigen-independent and contact-independent mechanisms. Transcriptomic analysis of infected IMOK cells revealed that Th17-associated soluble signals broadly attenuated epithelial innate immune and antibacterial responses, including pathways related to type II interferon signaling, chemokine production, and defense response to bacterium. Among these, Nos2 expression was significantly reduced upon Th17 co-culture and was accompanied by decreased nitric oxide (NO) production. Th17 cells expressed higher levels of Tgfb1 than Th1 cells, and elevated TGF-β concentrations were consistently observed under Th17 co-culture conditions associated with increased bacterial persistence. Neutralization of TGF-β was associated with a trend toward increased NO production and reduced intracellular Ec7.2 recovery relative to isotype-treated controls. Together, these findings identify a previously underappreciated role for Th17-associated signals in modulating epithelial defense against intracellular bacteria, in part through TGF-β-associated suppression of NO-associated antimicrobial responses, which may contribute to bacterial persistence in Th17-dominated mucosal environments.