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STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. The Journal of allergy and clinical immunology Pelham, S. J., Caldirola, M. S., Avery, D. T., Mackie, J., Rao, G., Gothe, F., Peters, T. J., Guerin, A., Neumann, D., Vokurkova, D., Hwa, V., Zhang, W., Lyu, S., Chang, I., Manohar, M., Nadeau, K. C., Gaillard, M. I., Bezrodnik, L., Iotova, V., Zwirner, N. W., Gutierrez, M., Al-Herz, W., Goodnow, C. C., Hernandez, A. V., Forbes, L., Hambleton, S., Deenick, E. K., Ma, C. S., Tangye, S. G. 2022

Abstract

BACKGROUND: Lymphocyte differentiation is regulated by co-ordinated actions of cytokines and signalling pathways. IL-21 activates STAT1, STAT3 and STAT5 and is fundamental for the differentiation of human B cells into memory cells and Ab secreting cells. While, STAT1 is largely non-essential and STAT3 is critical for this process, the role of STAT5 is unknown.OBJECTIVE: Delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells.METHODS: STAT activation was assessed by phosphoFACS. Differential gene expression was determined by RNA-Seq and qPCR. 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 Ig class switched B cells, CD21loTbet+ B cells and Tfh 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.CONCLUSION: Our 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 signalling, 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.

View details for DOI 10.1016/j.jaci.2022.04.011

View details for PubMedID 35469842