title: Transgenic expression of GM-CSF in T cells causes disseminated histiocytosis.
abstract: Recent studies highlight surprising roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. T-cell-derived GM-CSF is required for the differentiation of monocyte-derived inflammatory dendritic cells during inflammation and for the pathogenicity of IL-17 producing T helper cells in autoimmunity. To gain further insight into these findings, we engineered in vivo overexpression of GM-CSF specifically in T cells, under the control of the Lck promoter. Lck-GM-CSF transgenic mice displayed a dramatic phenotype, characterized by splenomegaly, lymphadenopathy, thymic atrophy, and multiple abnormalities in blood cell populations. Thymocyte differentiation was severely affected, and there was a dramatic increase in regulatory T cells in the thymus and peripheral lymphoid organs. Lck-GM-CSF transgenic mice developed a disseminated histiocytosis and had increased circulating IL-17 producing T helper cells-related cytokines. The pathological characteristics in Lck-GM-CSF transgenic mice resemble those of histiocytic human diseases, such as Langerhans cell histiocytosis. The etiology of many histiocytic disorders is unknown, but our findings suggest that over-production of GM-CSF by T cells could be a pathogenic factor and raise the possibility that GM-CSF may represent a novel therapeutic target.
authors.affiliation: Inflammation Division, the Reid Rheumatology Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Annemarie E
authors.initials: AE
authors.lastname: van Nieuwenhuijze
authors.affiliation: Inflammation Division, the Reid Rheumatology Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Elise
authors.initials: E
authors.lastname: Coghill
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia; Division of Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gray
authors.affiliation: Inflammation Division, the Reid Rheumatology Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Sandro
authors.initials: S
authors.lastname: Prato
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Inflammation Division, the Reid Rheumatology Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia; Rheumatology Unit, Melbourne Health, PO Royal Melbourne Hospital, Parkville, Australia. Electronic address: wicks@wehi.edu.au.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Wicks
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D015614:Histiocytosis / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor