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.