Full Papers
Single-cell landscape of immunological responses in CTLA4 haploinsufficiency patient after abatacept therapy
X. Jiang1, H. Zhao2, Y. He3, N. Wu4, X. Sun5, C. Shao6, D. Wu7, M. Shen8, X. Zeng9
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; and Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of Haematology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; and Center for Bioinformatics, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China. shenmpumch@163.com
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
CER19690
Full Papers
Received: 14/01/2026
Accepted : 13/07/2026
In Press: 05/08/2026
Abstract
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.
