A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.

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⁺ 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 c

SUBMITTER: Cabrera-Martinez B 

PROVIDER: S-EPMC12352292 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature