Soluble CD14 promotes Th17 expansion and differentiation through gamma-aminobutyric acid and expands non-canonical innate lymphoid cells

Interleukin-17 (IL-17) plays a central role in the pathogenesis of various autoimmune diseases. Soluble CD14 (sCD14), a marker of innate immune activation, is elevated in several inflammatory conditions. However, its influence on IL-17 production and the differentiation of Th17 cells remains poorly understood. We found that sCD14 enhances Th17-associated cytokine production and up-regulates critical transcription factors such as STAT3 and RORC. Notably, sCD14's effect on Th17 polarization was mediated indirectly through autologous sCD14-treated peripheral blood mononuclear cell (PBMC) supernatant (sCD14-PBMC-Sup). Additionally, we identified a distinct cytokine profile enriched for pro-inflammatory cytokines and chemokines in sCD14-treated T cells, further reinforcing the Th17-promoting role of sCD14. Interestingly, gamma-aminobutyric acid (GABA), a metabolite elevated in sCD14-treated monocytes, was identified as a potential contributor to Th17 polarization. GABA supplementation in T-cell cultures enhanced IL-17A secretion, indicating its role as a signaling molecule in T-cell differentiation. Our findings also revealed the expansion of innate lymphoid cell (ILC)2/3-like cells in T-cell cultures exposed to sCD14-PBMC-Sup and GABA, highlighting the potential role of monocytes in Th17-mediated immunity. Furthermore, while sCD14 promoted Th17 polarization, it simultaneously impaired T-cell activation and proliferation, suggesting an immunosuppressive effect mediated by soluble factors released from monocytes. These results underscore the dual role of sCD14 in modulating T-cell responses, promoting Th17 differentiation while suppressing T-cell effector functions. This study identifies a previously unrecognized role for sCD14 in promoting Th17 induction, highlighting its contribution to immune regulation and its potential as a therapeutic target in Th17-driven autoimmune conditions. Classification: Immunology.