title: Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions.
abstract: The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4(+) 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant for both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirm that STAT5B has fargreater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology.
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Alejandro
authors.identifier: 0000-0001-8068-2176
authors.initials: A
authors.lastname: Villarino
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Arian
authors.initials: A
authors.lastname: Laurence
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Gertraud W
authors.initials: GW
authors.lastname: Robinson
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonelli
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dema
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Shih
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Brooks
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse
keywords: STAT signaling; STAT5; T cells; autoimmunity; cell biology; cytokine; immunology; mouse; transcription factors