A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency
Berenice Cabrera-Martinez,
Josselyn E. Garcia-Perez,
Ryan M. Baxter,
Victor G. Lui,
Tusharkanti Ghosh,
Ahmet Eken,
Zander Kostka-Newman,
John Rhey Mhar Garcia,
Jeremy Rahkola,
Rachel L. Gessner,
Cullen M. Dutmer,
Jared Klarquist,
Eric M. Pietras,
Debashis Ghosh,
Sara A. Johnson,
Ross M. Kedl,
Elena W.Y. Hsieh
Affiliations
Berenice Cabrera-Martinez
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Josselyn E. Garcia-Perez
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA; CellCarta, Leuven, Belgium
Ryan M. Baxter
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Victor G. Lui
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA; Benaroya Research Institute, Seattle, WA, USA
Tusharkanti Ghosh
Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA
Ahmet Eken
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Zander Kostka-Newman
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
John Rhey Mhar Garcia
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Jeremy Rahkola
Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
Rachel L. Gessner
Medicine-Hematology, University of Colorado School of Medicine, Aurora, CO, USA
Cullen M. Dutmer
Department of Pediatrics, Section of Allergy and Immunology, School of Medicine, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA
Jared Klarquist
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Eric M. Pietras
Medicine-Hematology, University of Colorado School of Medicine, Aurora, CO, USA
Debashis Ghosh
Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA
Sara A. Johnson
Department of Pediatrics, Section of Allergy and Immunology, School of Medicine, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA
Ross M. Kedl
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Elena W.Y. Hsieh
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatrics, Section of Allergy and Immunology, School of Medicine, University of Colorado, Children’s Hospital Colorado, Aurora, CO, USA; Corresponding author
Summary: Here, we describe the use of a homologous knockin mouse model to further decipher the mechanism(s) of a novel human homozygous IL2RB hypomorphic mutation. Our model recapitulates the human immune dysregulation phenotype, showing decreased mutant interleukin-2Rβ (IL-2Rβ) cell-surface expression, impaired IL-2/15-dependent STAT5 signaling, elevated serum IL-2/15 levels, expanded effector memory CD8+ T cells, and severely reduced regulatory T cells (Tregs). Using mixed bone marrow chimeras (BMCs) and wild-type (WT) Treg transfers, we distinguish receptor-intrinsic from receptor-extrinsic immunopathogenesis. Both approaches suppress abnormal serum cytokine levels and autoimmunity without affecting endogenous mutant Tregs. Mutant animals receiving WT Tregs neonatally exhibit almost complete restoration of conventional T cell distribution, IL-2Rβ receptor surface expression, and STAT5 signal transduction, while BMC animals exhibit only partial restoration. Our findings demonstrate that CD8+ T cells and Tregs have distinct IL-2/15 ligand/receptor ratios and signaling thresholds required for proper development/function, revealing mechanistic insights applicable to immunotherapy for autoimmunity.
