title: 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 anti-apoptotic factors in the fibroblast-conditioned medium (FCM) revealed the presence of IL-10 and PGE2, but not IFN-beta, IL-2, or IL-15. Although recombinant IFN-beta, 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-beta or IFN-alpha failed to inhibit the anti-apoptotic 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 anti-apoptotic 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 anti-apoptotic effect, whereas medium from fibroblasts transfected with IFN-beta antisense oligonucleotides displayed the same anti-apoptotic 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.
authors: Division of Medical Oncology, Nagoya Memorial Hospital, Nagoya University School of Medicine, Nagoya, Japan.
authors: Kenji
authors: K
authors: Ina
authors: Kazuo
authors: K
authors: Kusugami
authors: Yasushi
authors: Y
authors: Kawano
authors: Tsuyoshi
authors: T
authors: Nishiwaki
authors: Zhonghui
authors: Z
authors: Wen
authors: Alessandro
authors: A
authors: Musso
authors: Gail A
authors: GA
authors: West
authors: Michio
authors: M
authors: Ohta
authors: Hidemi
authors: H
authors: Goto
authors: Claudio
authors: C
authors: Fiocchi
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007420:Intestine, Large / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; D007376:Interleukin-2; D019014:fas Receptor; D016753:Interleukin-10