Single-cell landscape of immunological responses in CTLA4 haploinsufficiency patient after abatacept therapy.

OBJECTIVES: Heterozygous germline mutations in the cytotoxic T lymphocyte antigen-4 (CTLA4) gene have been identified as the cause of a rare immune dysregulation syndrome in humans. Abatacept (CTLA4 Ig) has been approved for treatment of CTLA4 haploinsufficiency; however, its therapeutic mechanism remains unknown. METHODS: Following a 10-month observation period, abatacept treatment effectively alleviated disease symptoms without restoring CTLA4 expression and ligand capture. To gain insight into the immune response landscape associated with abatacept therapy, mass cytometry and single-cell RNA sequencing were performed on peripheral blood mononuclear cells from a patient with CTLA4 haploinsufficiency before and after treatment with abatacept. RESULTS: Although abatacept treatment can effectively alleviate patient's clinical symptoms, the addition of CTLA Ig in vitro does not restore its expression and ligand-capturing function. Immunological profiling results show that abatacept treatment modulated proportions of T and B naive and memory cells but did not significantly impact B-cell development. Additionally, both adaptive and innate immune activation were mitigated. Notably, abatacept treatment led to a reduction in expression of mitochondrial genes across various immune cells, suggesting a metabolic reprogramming effect. CONCLUSIONS: These results offer a theoretical foundation for utilisation of abatacept in CTLA4 haploinsufficiency and have significant implications for understanding the mechanism of immune checkpoints.