A Soluble Factor Produced by Lamina Propria Mononuclear Cells Is Required for TNF-α Enhancement of IFN-γ Production by T Cells

Abstract

AbstractThe role of TNF-α in the mucosal inflammation of Crohn’s disease has been demonstrated by the prolonged clinical responses and/or remissions among patients receiving i.v. infusion of anti-TNF-α. A correlation between TNF-α and elevated IFN-γ production is suggested by the reduction in the number of IFN-γ producing lamina propria mononuclear cells (LPMC) found in colonic biopsies from anti-TNF-α-treated patients. The aim of this study was to define the mechanism of TNF-α-augmented mucosal T cell IFN-γ production. In this paper we present evidence that cultured LPMC secrete a factor which acts on preactivated T cells in concert with TNF-α to augment IFN-γ production. This activity is independent of IL-12 and IL-18, the well-documented potentiators of IFN-γ expression, and is not produced by PBMC. Peripheral blood PHA-activated T cells incubated in supernatants from LPMC became responsive to TNF-α by increasing IFN-γ output upon stimulation. These results are consistent with a model in which LPMC, but not PBMC, release an unidentified substance when cultured in vitro with low dose IL-2. This substance can act on preactivated peripheral T cells, as well as on lamina propria T cells, conditioning them to respond to TNF-α by increased IFN-γ secretion upon stimulation. Expression of this factor in the gut mucosa could contribute to up-regulation of the Th1 response in the presence of TNF-α, and could be important for mucosal immunoregulation.