A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation

CTLA-4 is a critical immune checkpoint that maintains self-tolerance by regulating immune activation. Here, we describe the first case of homozygous CTLA-4 deficiency (CTLA4S172P/S172P), presenting with early-onset autoimmunity, lymphoproliferation, and growth failure. Immunological profiling revealed profound T- and B-cell dysregulation, characterized by T-cell hyperproliferation, a TH1-skewed helper T-cell phenotype, and expansion of activated and atypical B-cell subsets. The identified variant led to impaired CTLA-4 protein stability and enhanced lysosomal degradation, resulting in significantly reduced but still detectable total and surface expression and defective CD80 transendocytosis. Abatacept (CTLA-4-Ig) therapy effectively restored immune regulation and controlled disease activity. These findings expand the clinical and mechanistic spectrum of CTLA-4–related disorders, linking residual CTLA-4 function with the severity of immune dysregulation and emphasizing the therapeutic potential of targeted CTLA-4 modulation.