biostudies-literatureCabrera-Martinez BNIAID NIH HHSNIAMS NIH HHS115902https://www.ebi.ac.uk/biostudies/studies/S-EPMC12352292biostudies-literatureUnknown44(7)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.Cell reportsA hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.PMC12352292K23 AR070897R01 AI066121R01 AI126899R01 AI148919Lui VGEken AGhosh DCabrera-Martinez BGarcia JRMKedl RMGarcia-Perez JEKostka-Newman ZKlarquist JBaxter RMPietras EMGhosh TRahkola JGessner RLJohnson SADutmer CMHsieh EWYfalseA hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.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.2025-01-01T00:00:00Z2025 Jul2026-05-29T17:55:53.043Z2026-05-18T03:07:21.554ZS-EPMC123522924057036910.1016/j.celrep.2025.115902