Interaction of IL-2Rβ and γ _c Chains with Jak1 and Jak3: Implications for XSCID and XCID

TLDR

IL‑2 signaling depends on dimerization of IL‑2Rβ and the common γ chain, and mutations in γc are known to cause X‑linked severe combined immunodeficiency. The study shows that IL‑2, IL‑4, IL‑7, and IL‑9 trigger Jak1 and Jak3 activation, with Jak3 associating with IL‑2Rβ and γc, and that γc truncations or mutations that reduce γc‑Jak3 binding impair Jak3 activation, implying that γc or Jak3 defects can underlie X‑linked immunodeficiencies.

Abstract

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor β (IL-2Rβ) and common γ (γ c ) chains. Mutations of γ c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain γ c ), and IL-9 (whose receptor is shown here to contain γ c ) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2Rβ and γ c , respectively; IL-2 induced Jak3-IL-2Rβ and increased Jak3-γ c associations. Truncations of γ c , and a γ c , point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased γ c -Jak3 association. Thus, γ c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.