Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

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 (Treg) 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…

• GA
  Gordon and Betty Moore Foundation
• DF
  Deutsche Forschungsgemeinschaft
• NI
  National Institutes of Health
• CF
  Center for Environmental Microbial Interactions, California Institute of Technology
• NC
  National Center for Research Resources