Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa

Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. In this study, we uncovered a role for intestinal stromal products in the innate regulation of effector T cells. Stroma-conditioned media (S-CM) derived from the normal human intestinal stroma (transforming growth factor-beta (TGF-beta)(hi)/interleukin (IL)-6(lo)/IL-1 beta(lo)) significantly downregulated T-cell proliferation and interferon-gamma (IFN-gamma) production compared with S-CM derived from the inflamed Crohn's mucosa (TGF-beta(hi)/IL-6(hi)/IL-1 beta(hi)). Antibody neutralization studies showed that TGF-beta in normal S-CM inhibited T-cell proliferation and IFN-gamma production, whereas IL-6 plus IL-1 beta in Crohn's S-CM promoted T-cell proliferation, and IL-1 beta alone promoted IFN-gamma and IL-17 release. Importantly, normal S-CM inhibited T-bet expression, whereas Crohn's S-CM activated signal transducer and activator of transcription 3, suggesting that discordant T-cell responses are regulated at the transcription factor and signaling levels. These findings implicate stromal TGF-beta in the downregulation of T-cell 2responses in the normal intestinal mucosa, and stromal IL-6 and IL-1 beta in the promotion of Th1 and Th17 responses in the inflamed Crohn's mucosa, suggesting an innate regulatory function for the intestinal extracellular matrix.