In addition, we provide a visual comparison between the phenotypic features of CTLA-4 insufficiency and LRBA/DEF6 deficiency as checkpoint defects on one hand with other IEI with immune dysregulation, such as IPEX syndrome representing a “classical Tregopathy” and, as a contrast, two PIRDs that are linked to EBV susceptibility and malignancies and, as receptor-ligand pair, share the same pathomechanism, namely CD27 and CD70 deficiencies (Figure 2). The gene discussed is DEF6; the disease is immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.