Mehmet Cihangir Çatak, Salim Can, Satanay Hubrack, Feyza Bayram Catak, Asha Elmi, Royala Babayeva, Razin Amirov, Melek Yorgun Altunbaş, Sevgi Bilgiç Eltan, Deniz Ertem, Barış Yılmaz, Ahmet Koç, Batu Erman, Emine Bozkurtlar, Elif Karakoc-Aydiner, Ahmet Ozen, Bernice Lo, Safa Barış
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.