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Publications

Journal Article Epublish

PubMed: 42577896 DOI: 10.70962/jhi.20250175

TCR γδ cell-specific STAT5 gain of function induces a druggable chronic human immune dysregulation.

J Hum Immun 2(5):e20250175

Authors: Benedikt J Meyer, José Pedro Loureiro, Vladimir Nosi, Robin Hupfer, Adhideb Ghosh, Fabio Poletti, Annaïse Jauch, Julia Hirsiger, Caroline Berkemeier, Ingmar Heijnen, Jan Dirks, Ilaria Alborelli, Thomas Menter, Alexandar Tzankov, Christoph Hess, Alexander A Navarini, Christoph T Berger, Lucia Mori, Gennaro De Libero, Mike Recher

Affiliations

  • Immunodeficiency Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Experimental Immunology Laboratory, Department of Biomedicine, University of Basel and University Hospital, Basel, Switzerland.
  • Functional Genomics Center Zurich, ETH Zurich, and University of Zurich, Zurich, Switzerland.
  • Translational Immunology Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Laboratory Medicine, Division Medical Immunology, University Hospital Basel, Basel, Switzerland.
  • Laboratory Medicine, Division Diagnostic Hematology, University Hospital Basel, Basel, Switzerland.
  • Pathology, Institute of Medical Genetics & Pathology, University Hospital Basel, Basel, Switzerland.
  • Immunobiology Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Department of Medicine, Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK.
  • University Center for Immunology, University Hospital Basel, Basel, Switzerland.
  • Dermatology and Skin Laboratory, Department of Biomedicine Basel, University Hospital Basel, Basel, Switzerland.

Abstract

Within a prospective cohort of patients with immune dysregulation, we identified several individuals with chronically increased proportions of TCR γδ cells but normal peripheral lymphocyte counts. Among those, we identified one individual with a TCR γδ cell-specific heterozygous p.Y665F STAT5B gain-of-function mutation. Recurrent oral aphthous lesions, susceptibility to infection, arthralgia, and fatigue, were linked to relatively elevated numbers of γδ T cells expressing a Vγ9Vδ2 TCR, displaying hyperphosphorylation of STAT5 upon in vitro IL-2 stimulation. The TCR Vγ9Vδ2 cells exhibited enhanced proliferative response to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and dysregulated cytokine production. The TCR γδ cell transcriptome revealed the suppression of the default Th17 program, along with inhibition of RORC and MAF expression. The JAK inhibitor baricitinib improved clinical features of the observed immune dysregulation and reduced the frequency of peripheral TCR Vγ9Vδ2 cells. Thus, functionally altered TCR γδ cells may underlie chronic immune dysregulation of unknown molecular cause, demonstrated here to be amenable to tailored immune modulation.

MeSH

Cells