Functional Characterization of an <i>IL2RG</i> Variant, a Case Report of X‐Linked T‐ B + NK + SCID

The selective WT IL2RG expression in maternal B cells was consistent with the compromised IL-4R signaling (and compromised IL-21R signaling) in her offspring (the patient), as both IL-4 and IL-21 are critical for normal human B cell germinal center reactions but not for peripheral B cell homeostasis. The c.677 G > A IL2RG variant permitted normal NK cell degranulation and initial STAT5 phosphorylation but was incapable of sustaining normal NK cell activation and proliferation in vitro. As IL-2 and IL-15 induced in-vitro NK cell proliferation is primarily mediated through the low affinity βγ_c (CD122-CD132) complex, our data indicate the importance of high affinity IL-15Rα and IL-2 Rα mediated signaling in-vivo for sustaining NK cell numbers in X-linked SCID. Consequently, we further hypothesize that in cases of X-linked SCID, where even initial IL-15 and IL-2 STAT5 phosphorylation is compromised, in-vivo trans-presentation of IL-15 (and IL-2), via the high affinity IL-15Rα and IL-2Rα receptor subunits, will not be able to sustain normal peripheral NK cell numbers".