CTLA4 and lymphoproliferative syndrome: The clearest proof indicating that CTLA-4 is a major checkpoint for T cells comes from the observation that knocking out ctla4 in mice leads to a lethal lymphoproliferative syndrome [6,7], whilst in humans some immune dysregulation (such as Graves’ disease, autoimmune hypothyroidism, and type 1 diabetes) [8] and lymphoproliferative diseases [9] result from genetic alterations that cause CTLA-4 deficiency.