We identified germline heterozygous mutations in CTLA4 in members of four families with severe immune dysregulation. Human CTLA4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells and lymphocytic infiltration of target organs, mimicking Ctla4 homozygous mice. Patients also exhibited a B cell phenotype, with progressive loss of B cells and accumulation of autoreactive CD21lo B cells. This study demonstrates a critical quantitative role for CTLA-4 in human immune homeostasis.

CTLA4 haploinsufficiency and immune dysregulation

Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.

Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4

CTLA-4 Control over Foxp3+ Regulatory T Cell Function

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones.

Modeling CTLA4-linked autoimmunity with RNA interference in mice