Extracellular Matrix-associated Cytokines Regulate CD4(+) Effector T-cell Responses in Human Intestinal Mucosa

Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. Here we uncovered a role for intestinal stromal products in the innate regulation of effector T-cells. Stroma-conditioned media (S-CM) derived from normal human intestinal stroma (TGF-β(hi)/IL-6(lo)/IL-1β(lo)) significantly down-regulated T-cell proliferation and IFN-γ production compared to S-CM derived from inflamed Crohn’s mucosa (TGF-β(hi)/IL-6(hi)/IL-1β(hi)). Antibody neutralization studies showed that TGF-β in normal S-CM inhibited T-cell proliferation and IFN-γ production, whereas IL-6 plus IL-1β in Crohn’s S-CM promoted T-cell proliferation, and the IL-1β alone promoted IFN-γ and IL-17 release. Importantly, normal S-CM inhibited T-bet expression, whereas Crohn’s S-CM activated STAT3, suggesting that discordant T-cell responses are regulated at the transcription factor and signaling levels. These findings implicate stromal TGF-β in the down-regulation of T-cell responses in normal intestinal mucosa but stromal IL-6 and IL-1β in the promotion of Th1 and Th17 responses in inflamed Crohn’s mucosa, suggesting innate regulatory function for the intestinal extracellular matrix.