title: T-cell-restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung.
abstract: Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet(tg/wt) and T-bet(tg/tg)) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet(tg/wt) and T-bet(tg/tg) mice, respectively. T-bet(tg/tg) alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet(tg/tg) mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders.
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, University of Tokyo, Tokyo, Japan; Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan;
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iriguchi
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan; Kasumigaura Medical Center, Tsuchiura, Japan;
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, University of Tokyo, Tokyo, Japan; Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan;
authors.forename: Shin
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Medical Genetics.
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Matsuyama
authors.affiliation: Department of Nephrology, and.
authors.forename: Keigyou
authors.initials: K
authors.lastname: Yoh
authors.affiliation: Department of Anatomy and Embryology, University of Tsukuba, Tsukuba, Japan; International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan; Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan; and Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
mesh_terms: D000818:Animals; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000276:immunology*; D007150:Immunohistochemistry; D008168:Lung / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D011649:Pulmonary Alveolar Proteinosis / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor