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

Pelham, Simon J.; Caldirola, Maria Soledad; Avery, Danielle T.; Mackie, Joseph; Rao, Geetha; Gothe, Florian; Peters, Timothy J.; Guerin, Antoine; Neumann, David; Vokurkova, Doris; Hwa, Vivian; Zhang, Wenming; Lyu, Shu-Chen; Chang, Iris; Manohar, Monali; Nadeau, Kari C.; Gaillard, Maria Isabel; Bezrodnik, Liliana; Iotova, Violeta; Zwirner, Norberto Walter; Gutierrez, Mavel; Al-Herz, Waleed; Goodnow, Christopher C.; Vargas-Hernandez, Alexander; Satter, Lisa R. Forbes; Hambleton, Sophie; Deenick, Elissa K.; Ma, Cindy S. und Tangye, Stuart G. (2022): STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. In: Journal of Allergy and Clinical Immunology, Bd. 150, Nr. 4: S. 931-946

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 STATS 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, CD21(lo)Tbet(+) 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0091-6749
• Sprache: Englisch