Along with IL-2, IL-4, IL-7, IL-9, and IL-15, IL-21 shares the common cytokine receptor γ chain (Asao et al., 2001; Leonard, 2001), γc, which is mutated in humans with X-linked severe combined immunodeficiency (XSCID) (Noguchi et al., 1993), and defective IL-21 signaling substantially accounts for the defective B-cell function that is observed in XSCID patients (Ozaki et al., 2002; Recher et al., 2011), corresponding to IL-21’s ability to promote terminal B cell differentiation to plasma cells (Ozaki et al., 2004). Here, IL4 is linked to T-B+ severe combined immunodeficiency due to gamma chain deficiency.