{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cabrera-Martinez B"],"funding":["NIAID NIH HHS","NIAMS NIH HHS"],"pagination":["115902"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12352292"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["44(7)"],"pubmed_abstract":["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<sup>+</sup> 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<sup>+</sup> 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."],"journal":["Cell reports"],"pubmed_title":["A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency."],"pmcid":["PMC12352292"],"funding_grant_id":["K23 AR070897","R01 AI066121","R01 AI126899","R01 AI148919"],"pubmed_authors":["Lui VG","Eken A","Ghosh D","Cabrera-Martinez B","Garcia JRM","Kedl RM","Garcia-Perez JE","Kostka-Newman Z","Klarquist J","Baxter RM","Pietras EM","Ghosh T","Rahkola J","Gessner RL","Johnson SA","Dutmer CM","Hsieh EWY"],"additional_accession":[]},"is_claimable":false,"name":"A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.","description":"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<sup>+</sup> 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<sup>+</sup> 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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Jul","modification":"2026-05-29T17:55:53.043Z","creation":"2026-05-18T03:07:21.554Z"},"accession":"S-EPMC12352292","cross_references":{"pubmed":["40570369"],"doi":["10.1016/j.celrep.2025.115902"]}}