title: Local triggering of the ICOS coreceptor by CD11c(+) myeloid cells drives organ inflammation in lupus.
abstract: The inducible T cell costimulator (ICOS) is a potent promoter of organ inflammation in murine lupus. ICOS stimulates T follicular helper cell differentiation in lymphoid tissue, suggesting that it might drive autoimmunity by enhancing autoantibody production. Yet the pathogenic relevance of this mechanism remains unclear. It is also unknown whether other ICOS-induced processes might contribute to lupus pathology. Here we show that selective ablation of ICOS ligand (ICOSL) in CD11c(+) cells, but not in B cells, dramatically ameliorates kidney and lung inflammation in lupus-prone MRL.Fas(lpr) mice. Autoantibody formation was largely unaffected by ICOSL deficiency in CD11c(+) cells. However, ICOSL display by CD11c(+) cells in inflamed organs had a nonredundant role in protecting invading T cells from apoptosis by elevating activity of the PI3K-Akt signaling pathway, thereby facilitating T cell accrual. These findings reveal a mechanism that locally sustains organ inflammation in lupus.
authors.affiliation: Department of Medicine III, University of Bonn School of Medicine, 53127 Bonn, Germany. Electronic address: lino.teichmann@uni-bonn.de.
authors.forename: Lino L
authors.initials: LL
authors.lastname: Teichmann
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Cullen
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.affiliation: Institute for Immunology, Tsinghua University, Beijing, 100084, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Internal Medicine Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000096:biosynthesis; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D039521:CD11c Antigen; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt