STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis
Simon J Pelham 1, Maria Soledad Caldirola 2, Danielle T Avery 3, Joseph Mackie 1, Geetha Rao 3, Florian Gothe 4, Timothy J Peters 1, Antoine Guerin 1, David Neumann 5, Doris Vokurkova 5, Vivian Hwa 6, Wenming Zhang 7, Shu-Chen Lyu 8, Iris Chang 8, Monali Manohar 9, Kari C Nadeau 9, Maria Isabel Gaillard 2, Liliana Bezrodnik 10, Violeta Iotova 11, Norberto Walter Zwirner 12, Mavel Gutierrez 13, Waleed Al-Herz 14, Christopher C Goodnow 1, Alexander Vargas-Hernández 15, Lisa R Forbes Satter 15, Sophie Hambleton 16, Elissa K Deenick 1, Cindy S Ma 1, Stuart G Tangye 17
Affiliations
Affiliations
- 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.
- Garvan Institute of Medical Research, Darlinghurst, Australia.
- 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.
- Faculty of Medicine, University Hospital Hradec Kralove, Charles University, Prague, Czech Republic.
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
- 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.
- Sean N. Parker Center for Allergy and Asthma Research, Stanford, Calif; Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, Calif.
- 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.
- Department of Pediatrics, Medical University-Varna, Varna, Bulgaria; Pediatric Endocrinology, University Hospital "St Marina," Varna, Bulgaria.
- 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.
- Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
- 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.
- 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.
- Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia. Electronic address: s.tangye@garvan.org.au.
Abstract
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.
Keywords: CD21(lo) B cells; Human B-cell differentiation; IL-21; STAT5B; immune dysregulation; immunoglobulin class switching; inborn errors of immunity; plasma cell generation.
References
https://pubmed.ncbi.nlm.nih.gov/