Interaction of IL-2R$\beta$ and $\gamma_c$ Chains with Jak1 and Jak3: Implications for XSCID and XCID

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor $\beta$ (IL-2R$\beta$) and common $\gamma$ ($\gamma_c$) chains. Mutations of $\gamma_c$ can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain $\gamma_c$), and IL-9 (whose receptor is shown here to contain $\gamma_c$) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R$\beta$ and $\gamma_c$, respectively; IL-2 induced Jak3-IL-2R$\beta$ and increased Jak3-$\gamma_c$ associations. Truncations of $\gamma_c$, and a $\gamma_c$, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased $\gamma_c$-Jak3 association. Thus, $\gamma_c$ 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.