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

PELHAM, SIMON J.; CALDIROLA, MARÍA SOLEDAD; AVERY, DANIELLE T.; MACKIE, JOSEPH; RAO, GEETHA; GOTHE, FLORIAN; PETERS, TIMOTHY J.; GUERIN, ANTOINE; NEUMANN, DAVID; VOKURKOVA, DORIS; 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, CHIRSTOPHER C.; VARGAS-HERNÁNDEZ, ALEXANDER; FORBES SATTER, LISA R.; HAMBLETON, SOPHIE; DEENICK, ELISSA K.; TANGYE, STUART G.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

MOSBY-ELSEVIER

Año: 2022

0091-6749

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 todelineate unique roles ofSTAT5in activation and differentiation of human naive andmemory 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 CD41 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 notmemory,Bcells.Deletion of STAT5Bin B-cell lines diminished IL-21–mediated SOCS3 induction. PBMCs from STAT5B-null individuals contained expanded populations of immunoglobulin class-switched B cells, CD21loTbet1 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.