The inhibitory role of CTLA-4, especially for CD28-induced signaling, is evident in mice possessing a defective, non-functional CTLA-4 gene; these animals die at 2–3 weeks of age due to uncontrolled lymphocyte division, leading to massive inflammation in most organs, which is known as lymphoproliferative syndrome [53,54]. Here, CTLA4 is linked to lymphoproliferative syndrome.