STAT3 regulates NK and NKT cell differentiation through C-X3-C motif chemokine receptor 1 (CX3CR1) in hyper-IgE syndrome

Abstract Mutations in the signal transducer and activator of transcription 3 ( STAT3 ) gene are strongly associated with Hyper-IgE Syndrome (HIES), a rare immunodeficiency disorder characterized by elevated levels of IgE and recurrent infections. The molecular mechanisms of how STAT3 dysfunction contributes to the pathophysiology of HIES are complex and not fully elucidated, especially in natural killer (NK) cells, which are crucial for the immune response against infections and malignancies. Employing single-cell sequencing and flow cytometry, we investigated the effects of STAT3 mutations on immune cell development, differentiation, and function. Our findings revealed an increased population of CX3CR1 + CD57 + NK and NKT cells, suggesting their terminal differentiation and functional exhaustion. The trend of Th2 cell differentiation was identified in patients with STAT3 mutations and in STAT3 conditional knockout (CKO) mice. CUT&Tag analysis on CD4 + T cells from carriers of the STAT3 intron22 (2144 + 1G > A) mutation revealed enhanced binding of the variant STAT3 to the transcription start site of IL-4 , which provides an explanation for the elevated peripheral IgE levels observed in these STAT3 mutation patients. This study enhances our understanding of how STAT3 mutations drive immunological dysregulation in HIES. The identified changes in immunological signature and transcriptional mechanisms offer new insights into therapeutic targets for HIES.