Cytotoxic T lymphocyte antigen 4 (CTLA4) is a crucial negative regulator of T cells. A new study describes for the first time the consequences of CTLA4 mutations in humans. Six subjects from four unrelated families suffering from severe immune dysregulation were identified as having heterozygous germline mutations in CTLA4. Although the subjects had different mutations, they all had reduced CTLA4 mRNA and protein expression. The CTLA4 haploinsufficiency resulted in defective regulatory T cell function and hyperproliferative T cells, and lymphocytic infiltration of non-lymphoid organs was observed in these patients. B cells were also affected, with patients exhibiting circulating B cell lymphopenia and increased numbers of autoreactive CD21low B cells. The identification of these patients confirms the essential role of CTLA4 in maintaining B cell and T cell homeostasis.