Overactive STAT3 Dysregulates BCR Signalling and Drives Accumulation and Autoreactivity of Disease-Associated CD21low B Cells

Introduction Signal transducer and activator of transcription 3 (STAT3) regulates gene expression downstream of cytokine/hormone receptors. Germline heterozygous STAT3 gain-of-function mutations cause early-onset multi-organ autoimmune disease, including type-1 diabetes, autoimmune thyroid disease, rheumatoid arthritis, enteropathies, autoimmune cytopenias, and/or B memory lymphopenia, many pointing to B cell tolerance defects. In populations, JAK-STAT3 polymorphisms and STAT3 signalling cytokines are associated with increased risk of B cell-mediated autoimmune diseases, and the cytokines’ levels correlate with disease severity. Finally, STAT3 can be mutated to gain-of-function and is frequently constitutively active in B lymphomas. Despite this, B cell-intrinsic effects of overactive STAT3 remain unknown. Method and Results We address this in patients, and mice engineered to carry the most common pathogenic germline gain-of-function mutation, STAT3T716M, or STAT3G421R and STAT3K658N, also found in lymphomas/leukemias. Gain-of-function STAT3 causes aberrant accumulation of polyclonal CD21low B cells resembling those that accumulate with age, chronic infections, immunodeficiency, and autoimmune diseases. It causes accumulation of self-reactive SWHEL B cells recognising a blood cell surface autoantigen and, in humans, of VH4-34+ B cells recognising I/i self-antigen on blood cells. Using mouse and human BCR deep sequencing, flow cytometry, single-cell RNA, and chromatin immunoprecipitation sequencing, we show overactive STAT3 induces a surprising and striking dysregulation of BCR signalling molecules, many of which are direct pSTAT3 targets, and dysregulates BCR-induced Tbet and atypical differentiation. We use in vivo inhibition to test whether STAT3-mutant atypical B cells are specifically depleted by BCR-PI3K inhibition. In a first-in-kind analysis, we study additive effects of JAK-STAT3 and BCR polymorphisms on atypical B cell abundance and mRNA phenotypes in single-cell expression quantitative trait loci and RNA sequencing data from >1,000 individuals. Conclusion Our findings reveal the landscape of genes and proteins dysregulated by overactive STAT3 in B cells and a novel mechanism explaining over-accumulation of autoantibody-enriched CD21low B cells in multiple diseases characterised by JAK-STAT polymorphisms and/or over-abundant IL-6/IL-21 cytokines.

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Journal
Journal of Human Immunity
Published
2025-11-26
DOI
https://doi.org/10.70962/ascia2025abstract.p162
Primary Topic
Immunodeficiency and Autoimmune Disorders
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article
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article

Overactive STAT3 Dysregulates BCR Signalling and Drives Accumulation and Autoreactivity of Disease-Associated CD21low B Cells

Mandeep Singh, Erica G. Schmitt, Gülbû Uzel, Ignatius Chua et al.
Journal of Human Immunity
Immunodeficiency and Autoimmune Disorders
article

Overactive STAT3 Dysregulates BCR Signalling and Drives Accumulation and Autoreactivity of Disease-Associated CD21low B Cells

Mandeep Singh, Erica G. Schmitt, Gülbû Uzel, Ignatius Chua, Satu M. Mustjoki, Michael O’Sullivan, Peter McNaughton, Megan L. Faulks, Tiphanie P. Vogel, Joanne H. Reed, Danielle T. Avery, Christopher J. Jara, Owen M. Siggs, Timothy J. Peters, Blake Bowen, Hassan Abolhassani, S. Cindy, Megan A. Cooper, Kahn Preece, Robert Brink, Joseph E. Powell, Joseph Mackie, Leena Kainulainen, Katherine Jackson, Christopher C. Goodnow, Stuart G. Tangye, Mikko Seppänen, Anna Förster, Jennifer W. Leiding, Etienne Masle‐Farquhar, Kaarina Heiskanen, Daniel Suan, Shannon Brothers, Ania Moxon
article en

Abstract

Introduction Signal transducer and activator of transcription 3 (STAT3) regulates gene expression downstream of cytokine/hormone receptors. Germline heterozygous STAT3 gain-of-function mutations cause early-onset multi-organ autoimmune disease, including type-1 diabetes, autoimmune thyroid disease, rheumatoid arthritis, enteropathies, autoimmune cytopenias, and/or B memory lymphopenia, many pointing to B cell tolerance defects. In populations, JAK-STAT3 polymorphisms and STAT3 signalling cytokines are associated with increased risk of B cell-mediated autoimmune diseases, and the cytokines’ levels correlate with disease severity. Finally, STAT3 can be mutated to gain-of-function and is frequently constitutively active in B lymphomas. Despite this, B cell-intrinsic effects of overactive STAT3 remain unknown. Method and Results We address this in patients, and mice engineered to carry the most common pathogenic germline gain-of-function mutation, STAT3T716M, or STAT3G421R and STAT3K658N, also found in lymphomas/leukemias. Gain-of-function STAT3 causes aberrant accumulation of polyclonal CD21low B cells resembling those that accumulate with age, chronic infections, immunodeficiency, and autoimmune diseases. It causes accumulation of self-reactive SWHEL B cells recognising a blood cell surface autoantigen and, in humans, of VH4-34+ B cells recognising I/i self-antigen on blood cells. Using mouse and human BCR deep sequencing, flow cytometry, single-cell RNA, and chromatin immunoprecipitation sequencing, we show overactive STAT3 induces a surprising and striking dysregulation of BCR signalling molecules, many of which are direct pSTAT3 targets, and dysregulates BCR-induced Tbet and atypical differentiation. We use in vivo inhibition to test whether STAT3-mutant atypical B cells are specifically depleted by BCR-PI3K inhibition. In a first-in-kind analysis, we study additive effects of JAK-STAT3 and BCR polymorphisms on atypical B cell abundance and mRNA phenotypes in single-cell expression quantitative trait loci and RNA sequencing data from >1,000 individuals. Conclusion Our findings reveal the landscape of genes and proteins dysregulated by overactive STAT3 in B cells and a novel mechanism explaining over-accumulation of autoantibody-enriched CD21low B cells in multiple diseases characterised by JAK-STAT polymorphisms and/or over-abundant IL-6/IL-21 cytokines.

Journal of Human ImmunityVol. 1(ASCIA2025)
St. Louis Children's Hospital (US), Karolinska University Hospital (SE), University of Helsinki (FI), Garvan Institute of Medical Research (AU), Johns Hopkins University (US), Washington University in St. Louis (US), University of South Florida (US), SUNY Geneseo (US), Helsinki University Hospital (FI), Fiona Stanley Hospital (AU), Turku University Hospital (FI), Christchurch Hospital (NZ), Canterbury Health Laboratories (NZ), Johns Hopkins All Children's Hospital (US), Futures Group (United States) (US), St Vincent's Clinic (AU), National Institute of Allergy and Infectious Diseases (US), Starship Children's Health (NZ), Westmead Institute for Medical Research (AU), Melior Discovery (United States) (US), Marymount University (US)
Openalex Percentile: Top 59%
Immunodeficiency and Autoimmune Disorders
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