2011 journal article
Antigen-Presenting Cell Production of IL-10 Inhibits T-Helper 1 and 17 Cell Responses and Suppresses Colitis in Mice
GASTROENTEROLOGY, 141(2), 653–U764.
author keywords: Mouse Model; Inflammatory Bowel Disease; Immune Response; Microbiota
MeSH headings : Adaptive Immunity; Animals; Antigen-Presenting Cells / drug effects; Antigen-Presenting Cells / metabolism; Antigens, Bacterial / immunology; CD11b Antigen / metabolism; CD4-Positive T-Lymphocytes / metabolism; Cells, Cultured; Colitis / immunology; DNA-Binding Proteins / deficiency; DNA-Binding Proteins / genetics; Forkhead Transcription Factors / metabolism; Germ-Free Life; Immunity, Innate; Interferon-gamma / metabolism; Interleukin-10 / deficiency; Interleukin-10 / genetics; Interleukin-10 / immunology; Interleukin-10 / metabolism; Interleukin-10 / pharmacology; Interleukin-12 / metabolism; Interleukin-17 / metabolism; Mice; Mice, Knockout; RNA, Messenger / metabolism; Signal Transduction; Smad Proteins; T-Box Domain Proteins / metabolism; T-Lymphocytes, Regulatory / cytology; Th1 Cells / immunology; Th17 Cells / immunology; Transforming Growth Factor beta / metabolism; Tretinoin / physiology
europepmc.org (repository)
Source: Web Of Science
Added: August 6, 2018
Background & AimsMice that are deficient in interleukin (IL)-10 develop colitis, mediated by T-helper (Th)1 and Th17 cells, and IL-10–producing regulatory T (Treg) cells suppress colitis, implicating IL-10 in maintaining mucosal homeostasis. We assessed the relative importance of immunoregulatory IL-10 derived from T cells or from antigen presenting cells (APCs) in development of intestinal inflammation.MethodsCD4+ cells from germ-free (GF) or specific pathogen-free (SPF) IL-10−/− or wild-type mice were injected into IL-10−/−, Rag2−/− mice or Rag2−/− mice that express IL-10. After 6–8 weeks, we evaluated inflammation, spontaneous secretion of cytokines from colonic tissue, and mRNA levels of the transcription factor T-bet and the immunoregulatory cytokine transforming growth factor (TGF)-β. CD4+ T cells were co-cultured with bacterial lysate-pulsed APCs and assayed for cytokine production, FoxP3 expression, and TGF-β-mediated Smad signaling.ResultsCD4+ cells from GF or SPF IL-10−/− or wild-type mice induced more severe colitis and higher levels of inflammatory cytokines in IL-10−/−, Rag2−/− mice than in IL-10-replete, Rag2−/− mice. Co-cultures of IL-10−/− or wild-type CD4+ T cells plus bacterial lysate-pulsed APCs from IL-10−/− mice contained more interferon (IFN)-γ, IL-12/23p40, and IL-17 than co-cultures of the same T cells plus APCs from wild-type mice. CD11b+ APCs were required for these effects. Blocking IL-10 receptors increased production of IFN-γ and IL-12/23p40 whereas exogenous IL-10 suppressed these cytokines. IL-10–producing APCs induced TGF-β-mediated, retinoic acid-dependent, differentiation of FoxP3+ Treg cells, whereas blocking the retinoic acid receptor, in vitro and in vivo, reduced proportions of FoxP3+ Treg cells.ConclusionsIL-10 produced by APCs regulates homeostatic T-cell responses to commensal bacteria. Mice that are deficient in interleukin (IL)-10 develop colitis, mediated by T-helper (Th)1 and Th17 cells, and IL-10–producing regulatory T (Treg) cells suppress colitis, implicating IL-10 in maintaining mucosal homeostasis. We assessed the relative importance of immunoregulatory IL-10 derived from T cells or from antigen presenting cells (APCs) in development of intestinal inflammation. CD4+ cells from germ-free (GF) or specific pathogen-free (SPF) IL-10−/− or wild-type mice were injected into IL-10−/−, Rag2−/− mice or Rag2−/− mice that express IL-10. After 6–8 weeks, we evaluated inflammation, spontaneous secretion of cytokines from colonic tissue, and mRNA levels of the transcription factor T-bet and the immunoregulatory cytokine transforming growth factor (TGF)-β. CD4+ T cells were co-cultured with bacterial lysate-pulsed APCs and assayed for cytokine production, FoxP3 expression, and TGF-β-mediated Smad signaling. CD4+ cells from GF or SPF IL-10−/− or wild-type mice induced more severe colitis and higher levels of inflammatory cytokines in IL-10−/−, Rag2−/− mice than in IL-10-replete, Rag2−/− mice. Co-cultures of IL-10−/− or wild-type CD4+ T cells plus bacterial lysate-pulsed APCs from IL-10−/− mice contained more interferon (IFN)-γ, IL-12/23p40, and IL-17 than co-cultures of the same T cells plus APCs from wild-type mice. CD11b+ APCs were required for these effects. Blocking IL-10 receptors increased production of IFN-γ and IL-12/23p40 whereas exogenous IL-10 suppressed these cytokines. IL-10–producing APCs induced TGF-β-mediated, retinoic acid-dependent, differentiation of FoxP3+ Treg cells, whereas blocking the retinoic acid receptor, in vitro and in vivo, reduced proportions of FoxP3+ Treg cells. IL-10 produced by APCs regulates homeostatic T-cell responses to commensal bacteria.
