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.

Department of Pediatrics Baylor College of Medicine Houston Tex; Department of Allergy Immunology and Retrovirology William T Shearer Center for Human Immunobiology Texas Children's Hospital Houston Tex

Department of Pediatrics Division of Endocrinology Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine Cincinnati Ohio

Department of Pediatrics Faculty of Medicine Kuwait University Kuwait City Kuwait

Department of Pediatrics Medical University Varna Varna Bulgaria; Pediatric Endocrinology University Hospital St Marina Varna Bulgaria

Department of Surgery Stanford University Stanford Calif

Division of Pulmonary Allergy and Critical Care Medicine Stanford University Stanford Calif; Sean N Parker Center for Allergy and Asthma Research Stanford Calif

Faculty of Medicine University Hospital Hradec Kralove Charles University Prague Czech Republic

Garvan Institute of Medical Research Darlinghurst Australia

Garvan Institute of Medical Research Darlinghurst Australia; St Vincent's Clinical School Faculty of Medicine and Health University of New South Wales Sydney Australia

Grupo de Inmunología Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas Hospital de Niños Dr Ricardo Gutierrez Buenos Aires Argentina

Grupo de Inmunología Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas Hospital de Niños Dr Ricardo Gutierrez Buenos Aires Argentina; Center for Clinical Immunology Buenos Aires Argentina

Immunity and Inflammation Theme Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne United Kingdom; Department of Pediatrics Dr von Hauner Children's Hospital University Hospital Ludwig Maximilians Universität Munich Munich Germany

Immunity and Inflammation Theme Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne United Kingdom; Great North Children's Hospital Newcastle upon Tyne Hospitals National Health Service Foundation Trust Newcastle upon Tyne United Kingdom

Instituto de Biología y Medicina Experimental Laboratorio de Fisiopatología de la Inmunidad Innata Buenos Aires Argentina; Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales Universidad de Buenos Aires Argentina

Rocky Mountain Hospital for Children Presbyterian St Luke's Medical Center Denver Colo

Sean N Parker Center for Allergy and Asthma Research Stanford Calif; Division of Pulmonary Allergy and Critical Care Medicine Stanford University Stanford Calif

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