Somatic STAT5B^N642H mutations shape variable immune landscapes resulting in heterogenous immune diseases - 03/04/26

Doi : 10.1016/j.jaci.2025.12.993

Sarah Grün, MSc ^a,^b,^c, Anne Rensing-Ehl, MD ^a, Tobias Suske, PhD ^d, Julian Wolter-Mess, PhD ^b,^c,^e, Jonathan Gehrig, MSc ^a,^b, Jasmin Mann, MSc ^a,^b, Christoph König, MSc ^a,^b, Mathias Hauri, MD, PhD ^f, Maximilian Heeg, MD ^a,^g, Timothy Ronan Leahy, MD ^h, David Genevieve, MD, PhD ⁱ, Jean-Baptiste Gaillard, PharmD ^j, Martin Broly, MD ^k, Arnaud Bourdin, MD, PhD ^l, Carla Castro, PhD ^a, Lea Seidel, MSc ^b,^m, Bertram Bengsch, MD, PhD ^c,^m, Peter Aichele, PhD ^a, Kristoffer Weißert, PhD ^a, Juncal Fernandez-Orth, PhD ⁿ, Vincent Schipperges, PhD ^o, Geoffroy Andrieux, PhD ^o, Melanie Boerries, MD, PhD ^o,^p, Nina Cabezas-Wallscheid, PhD ^c,^e, Miriam Erlacher, MD, PhD ^g,^q, Roland Elling, MD ^g, Carsten Speckmann, MD ^a,^g, Lara Heller, PhD ^r,^s, Björn Schulte, PhD ^r,^s, Myriam Lorenz, PhD ^t, Klaus Schwarz, MD ^t,^u, Richard Moriggl, MD ^v, Stephan Ehl, MD ^a,^c,^⁎

^a Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

^b Faculty of Biology, University of Freiburg, Freiburg, Germany

^c Signalling Research Centre CIBSS, University of Freiburg, Freiburg, Germany

^d Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria

^e Max-Planck-Institute for Immunobiology and Epigenetics, Freiburg, Germany

^f Division of Stem Cell Transplantation, University Children’s Hospital Zurich, Eleonore Foundation & Children’s Research Center (CRC), Zurich, Switzerland

^g Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

^h Children’s Health Ireland at Crumlin and University of Dublin, Trinity College Dublin, Dublin, Ireland

ⁱ Montpellier University, INSERM U1183, IRMB, IHU Immu4Cure, Clinical Genetic Department, Montpellier University Hospital, Montpellier, France

^j Department of Molecular Genetics and Cytogenomics, University Hospital of Montpellier, Montpellier, France

^k University of Montpellier, INSERM U1183, IRMB, IHU Immun4Cure, French National Reference Center of Autoinflammatory Diseases and Amyloidosis (CeRéMAIA), CHU Montpellier, Department of Molecular Genetics and Cytogenomics, National Reference Laboratory of Autoinflammatory Diseases, Montpellier, France

^l University of Montpellier, Department of Respiratory Disease, PhyMedExp, INSERM U1046, CNRS UMR 9214, CHU Montpellier, Montpellier, France

^m Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

ⁿ Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

^o Institute of Medical Bioinfomatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

^p German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between DKFZ and Medical Center–University of Freiburg, Freiburg, Germany

^q Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany

^r Center of Human Genetics Tübingen, Tübingen, Germany

^s CeGaT GmbH Tübingen, Tübingen, Germany

^t Institute for Transfusion Medicine, University of Ulm, Ulm, Germany

^u Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wurttemberg—Hessen, Ulm, Germany

^v Department of Biosciences & Medical Biology, Paris Lodron University Salzburg, Salzburg, Austria

^∗ Corresponding author: Stephan Ehl, MD, Center for Chronic Immunodeficiency, Breisacher Str. 115, 79106 Freiburg, Germany. Center for Chronic Immunodeficiency Breisacher Str. 115 Freiburg 79106 Germany

Abstract

Background

Inborn errors of immunity are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking inborn errors of immunity. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5B ^N642H was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined.

Objective

We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes.

Methods

We investigated 3 new patients—including one adult—with STAT5B ^N642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5B ^N642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes.

Results

Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2–mediated proliferation, effector differentiation, and oligoclonal T-cell expansions. In mice, a few mutant hematopoietic stem cells reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T-cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients.

Conclusion

A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.

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Key words : STAT5B, somatic mosaicism, hematopoietic stem cells, clonal hematopoiesis, immune dysregulation, T-cell lymphoproliferation, autoimmunity, atopy, mTOR inhibition

Abbreviations used : Bcl-2, BM, FACS, HD, HSC, HSCT, JAK, LSK, mTOR, NK, pY, RNA-Seq, T-bet, WT

Plan

Somatic STAT5B ^N642H mosaicism associated with atopic and/or autoimmune-lymphoproliferative phenotypes

Lineage distribution of STAT5B ^N642H mosaicism correlates with clinical phenotype

STAT5B ^N642H enhances IL-2–induced proliferation in patient CD8 T cells

STAT5B ^N642H drives effector T-cell differentiation and oligoclonal expansion

STAT5B ^N642H conveys variable growth advantage to different leukocyte populations

Variable growth advantage of STAT5B ^N642H -expressing hematopoietic precursors in different lineage trajectories

STAT5B ^N642H T cells in chimeric mice mimic patient T-cell phenotype

Signaling blockade controls excessive proliferation of patient STAT5B ^N642H T cells in vitro and in vivo

Evolution of lineage-specific mosaicism after HSCT confirms the variability of clonal dominance conferred by STAT5B ^N642H

Discussion

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Vol 157 - N° 4

P. 964-976 - avril 2026 Retour au numéro

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Somatic STAT5B^N642H mutations shape variable immune landscapes resulting in heterogenous immune diseases - 03/04/26

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