Somatic STAT5BN642H mutations shape variable immune landscapes resulting in heterogenous immune diseases

BACKGROUND: was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined. OBJECTIVE: We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes. METHODS: mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes. RESULTS: Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2-mediated proliferation, effector differentiation, and oligoclonal T-cell expansions. In mice, a few mutant hematopoietic stem cells reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T-cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients. CONCLUSION: A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.