Although CTLA-4 can be expressed at lower levels in other cell types and has been suggested as a negative regulator for naïve T cell activation, lineage-specific deletion of the Ctla4 gene in Foxp3+ Tregs results in development of systemic lymphoproliferation, fatal autoimmune disease, and potent tumor immunity.11 These data are consistent with the notion that the predominant function of CTLA-4 is Treg-intrinsic. This evidence concerns the gene FOXP3 and autoimmune disease.