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.