title: Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells.
abstract: The Runx1 transcription factor is abundantly expressed in naive T cells but rapidly downregulated in activated T cells, suggesting that it plays an important role in a naive stage. In the current study, Runx1(-/-)Bcl2(tg) mice harboring Runx1-deleted CD4(+) T cells developed a fatal autoimmune lung disease. CD4(+) T cells from these mice were spontaneously activated, preferentially homed to the lung, and expressed various cytokines, including IL-17 and IL-21. Among these, the deregulation of IL-21 transcription was likely to be associated with Runx binding sites located in an IL-21 intron. IL-17 produced in Runx1-deleted cells mobilized innate immune responses, such as those promoted by neutrophils and monocytes, whereas IL-21 triggered humoral responses, such as plasma cells. Thus, at an initial stage, peribronchovascular regions in the lung were infiltrated by CD4(+) lymphocytes, whereas at a terminal stage, interstitial regions were massively occupied by immune cells, and alveolar spaces were filled with granular exudates that resembled pulmonary alveolar proteinosis in humans. Mice suffered from respiratory failure, as well as systemic inflammatory responses. Our data indicate that Runx1 plays an essential role in repressing the transcription of cytokine genes in naive CD4(+) T cells and, thereby, maintains cell quiescence.
authors.affiliation: Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Won Fen
authors.initials: WF
authors.lastname: Wong
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kohu
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Ryushi
authors.initials: R
authors.lastname: Tazawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tanaka
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kon
authors.forename: Tomo
authors.initials: T
authors.lastname: Funaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Sugahara-Tobinai
authors.forename: Chung Yeng
authors.initials: CY
authors.lastname: Looi
authors.forename: Shota
authors.initials: S
authors.lastname: Endo
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Sonoko
authors.initials: S
authors.lastname: Habu
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality; D019169:Jurkat Cells; D008171:Lung Diseases / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; C493728:RUNX1 protein, human