期刊
SCIENCE
卷 345, 期 6204, 页码 1623-1627出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1255904
关键词
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资金
- Intramural Research Program, NIH Clinical Center
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Cancer Institute [HHSN261200800001E]
- National Institute of Allergy and Infectious Diseases [5R01HL113304-01, AI071087, AI095848, AI061093]
- National Health and Medical Research Council of Australia
- Cancer Council NSW
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (T-reg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.
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