The crucial role of the negative regulation by CLTA‐4 is illustrated by the lethal autoimmunity developed by Ctla4‐deficient mice.124 CTLA‐4 resides in intracellular vesicles on Treg and is released and mobilized to the cell surface after TCR stimulation, where it works as an “off” switch when bound to either CD80 or CD86 on the surface of antigen‐presenting cells.125, 126 CTLA‐4 haploinsufficiency or impaired ligand binding results in a complex syndrome presenting with features of both autoimmunity and immunodeficiency.127. This evidence concerns the gene CD80 and Autoimmunity.