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STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis

Lookup NU author(s): Dr Florian Gothe, Professor Sophie Hambleton

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Abstract

© 2022 American Academy of Allergy, Asthma & ImmunologyBackground: 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.

Publication metadata

Author(s): Pelham SJ, Caldirola MS, Avery DT, Mackie J, Rao G, Gothe F, Peters TJ, Guerin A, Neumann D, Vokurkova D, Hwa V, Zhang W, Lyu S-C, Chang I, Manohar M, Nadeau KC, Gaillard MI, Bezrodnik L, Iotova V, Zwirner NW, Gutierrez M, Al-Herz W, Goodnow CC, Vargas-Hernandez A, Forbes Satter LR, Hambleton S, Deenick EK, Ma CS, Tangye SG

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2022

Volume: 150

Issue: 4

Pages: 931-946

Print publication date: 01/10/2022

Online publication date: 22/04/2022

Acceptance date: 14/04/2022

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.jaci.2022.04.011

DOI: 10.1016/j.jaci.2022.04.011

PubMed id: 35469842

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