title: Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells.
abstract: STAT5A and STAT5B are highly homologous proteins whose distinctive roles in human immunity remain unclear. However, STAT5A sufficiency cannot compensate for STAT5B defects, and human STAT5B deficiency, a rare autosomal recessive primary immunodeficiency, is characterized by chronic lung disease, growth failure and autoimmunity associated with regulatory T cell (Treg) reduction. We therefore hypothesized that STAT5A and STAT5B play unique roles in CD4(+) T cells. Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells and down-regulated Bcl-X only in STAT5A knockdown T cells. Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype. These results indicate that STAT5B and STAT5A act partly as non-redundant transcription factors and that STAT5B is more critical for Treg maintenance and function in humans.
authors.affiliation: Division of Immunology and Allergy, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Jenks
authors.forename: Scott
authors.initials: S
authors.lastname: Seki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kanai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huang
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Morgan
authors.forename: Renata C
authors.initials: RC
authors.lastname: Scalco
authors.forename: Ruhi
authors.initials: R
authors.lastname: Nath
authors.forename: Robert
authors.initials: R
authors.lastname: Bucayu
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Dina
authors.initials: D
authors.lastname: Ramadan
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Jorge
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Ron
authors.initials: R
authors.lastname: Rosenfeld
authors.forename: Kari C
authors.initials: KC
authors.lastname: Nadeau
mesh_terms: D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D055815:Young Adult; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D007334:Insulin-Like Growth Factor I
keywords: FOXP3; Regulatory T cells (Treg); STAT5; T cell development; T cell receptor excision circles; TREC; Treg; forkhead box P3; regulatory T cell