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http://purl.uniprot.org/citations/35469842http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/35469842http://www.w3.org/2000/01/rdf-schema#comment"

Background

Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown.

Objectives

This study sought to delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells.

Methods

STAT activation was assessed by phospho-flow cytometry cell sorting. Differential gene expression was determined by RNA-sequencing and quantitative PCR. The requirement for STAT5B in B-cell and CD4+ T-cell differentiation was assessed using CRISPR-mediated STAT5B deletion from B-cell lines and investigating primary lymphocytes from individuals with germline STAT5B mutations.

Results

IL-21 activated STAT5 and strongly induced SOCS3 in human naive, but not memory, B cells. Deletion of STAT5B in B-cell lines diminished IL-21-mediated SOCS3 induction. PBMCs from STAT5B-null individuals contained expanded populations of immunoglobulin class-switched B cells, CD21loTbet+ B cells, and follicular T helper cells. IL-21 induced greater differentiation of STAT5B-deficient B cells into plasmablasts in vitro than B cells from healthy donors, correlating with higher expression levels of transcription factors promoting plasma cell formation.

Conclusions

These findings reveal novel roles for STAT5B in regulating IL-21-induced human B-cell differentiation. This is achieved by inducing SOCS3 to attenuate IL-21 signaling, and BCL6 to repress class switching and plasma cell generation. Thus, STAT5B is critical for restraining IL-21-mediated B-cell differentiation. These findings provide insights into mechanisms underpinning B-cell responses during primary and subsequent antigen encounter and explain autoimmunity and dysfunctional humoral immunity in STAT5B deficiency."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2022.04.011"xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Gutierrez M."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Zhang W."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Rao G."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Hwa V."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Neumann D."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Hambleton S."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Vargas-Hernandez A."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Peters T.J."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Goodnow C.C."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Ma C.S."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Tangye S.G."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Lyu S.C."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Nadeau K.C."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Avery D.T."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Deenick E.K."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Chang I."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Al-Herz W."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Manohar M."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Guerin A."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Bezrodnik L."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Caldirola M.S."xsd:string
http://purl.uniprot.org/citations/35469842http://purl.uniprot.org/core/author"Gaillard M.I."xsd:string
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