Intestinal Fibroblast-Derived IL-10 Increases Survival of Mucosal T Cells by Inhibiting Growth Factor Deprivation- and Fas-Mediated Apoptosis

Abstract

Mucosal T cells are essential to immune tolerance in the intestine, an organ constantly exposed to large amounts of dietary and bacterial Ags. We investigated whether local fibroblasts affect mucosal T cell survival, which is critical for maintenance of immune tolerance. Coculture with autologous fibroblasts significantly increased viability of mucosal T cells by inhibiting IL-2 deprivation- and Fas-mediated apoptosis, an effect that was both contact- and secreted product-dependent. Investigation of antiapoptotic factors in the fibroblast-conditioned medium (FCM) revealed the presence of IL-10 and PGE2, but not IFN-β, IL-2, or IL-15. Although recombinant IFN-β, but not PGE2, effectively prevented T cell apoptosis, neutralizing Ab studies showed that only IL-10 blockade significantly increased T cells apoptosis, whereas neutralizing IFN-β or IFN-α failed to inhibit the antiapoptotic effect of FCM. To confirm that fibroblast-derived IL-10 was responsible for preserving mucosal T cell viability, IL-10 mRNA was demonstrated in fibroblasts by Southern blotting and RT-PCR. When FCM was submitted to HPLC fractionation, only the peak matching rIL-10 contained the antiapoptotic activity, and this was eliminated by treatment with an IL-10-neutralizing Ab. Finally, when fibroblasts were transiently transfected with IL-10 antisense oligonucleotides, the conditioned medium lost its T cell antiapoptotic effect, whereas medium from fibroblasts transfected with IFN-β antisense oligonucleotides displayed the same antiapoptotic activity of medium from untransfected fibroblasts. These results indicate that local fibroblast-derived IL-10 is critically involved in the survival of mucosal T cells, underscoring the crucial importance of studying organ-specific cells and products to define the mechanisms of immune homeostasis in specialized tissue microenvironments like the intestinal mucosa.

Mucosal IL-10 and TGF-β play crucial roles in preventing LPS-driven, IFN-γ–mediated epithelial damage in human colon explants

“…In addition, we demonstrate in this study that IL-10 was not only produced, but also secreted, in the culture medium of mucosa explant cultures. The current prevailing concept in the literature is that IL-10 is synthesized in the human intestinal mucosa mainly by immune cellsincluding regulatory T cells, B cells, macrophages, and dendritic cells -and also by fibroblasts and epithelial cells (15,(20)(21)(22), a distribution analog to that previously reported in the mouse intestinal mucosa (23)(24)(25)(26)(27)(28)(29). Here we show that IL-10 was constitutively synthesized and secreted in the human colonic mucosa by resident cells, including epithelial cells.…”

“…It is inappropriate to infer the mucosal effect of IL-10 produced in situ from experiments based on systemic administration. This issue has already been raised by Ina et al (15), who showed, in a coculture model system, the importance of studying organ-specific cells to define the mechanisms of intestinal mucosa homeostasis.…”

The role of IL-10 in microbiome-associated immune modulation and disease tolerance

“…In addition, mesangial cells and mesenchymal cells may contribute to the IL-10 production [156,157]. Thus, it is plausible that IL-10 influences the local microenvironment through tissue-specific regulatory mechanisms.…”

Immune-non Immune Networks in Intestinal Inflammation

“…Intestinal myofibroblasts furthermore seem to be able to influence the rate of apoptosis of immune cells [46][47][48]. Thereby they might influence the balance between different T-cell subsets which could be another important influence factor on inflammation and the mucosal immune system.…”