DIFFERENTIAL SIGNALING THROUGH THE IL-2 AND IL-4 RECEPTORS IN LYMPHOCYTES FROM PATIENTS WITH X-SCID: EVIDENCE FOR A γ_c INDEPENDENT IL-4 RECEPTOR. • 73

The common γ chain (γ_c) is a component of the receptors for the cytokines IL-2, IL-4, IL-7, IL-9 and IL-15. Mutations inγ_c result in X-linked severe combined immune deficiency (X-SCID), with characteristic profound defects of cellular and humoral immunity. The interaction of IL-2 with the high affinity IL-2 receptor (IL-2R), comprised of an IL-2Rα, IL-2Rβ, and γ_c, is essential for T cell responses. The IL-4 receptor has been found to contain an IL-4Rα andγ_c. IL-4 stimulates a diverse array of biological functions, including proliferation and differentiation of B cells, T cells and mast cells. It has recently been shown that one of the first events induced by ligand interaction with either the IL-2R or IL-4R is tyrosine phosphorylation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 associates with both IL-2Rβ and IL-4Rα while Jak3 associates specifically withγ_c. We assessed activation of Jak1 and Jak3 in Epstein-Barr virus transformed B cells from normal individuals and X-SCID patients. As expected, Jak3 as well as Jak1 were not activated by IL-2 in cell lines derived from patients lacking γ_c transcripts (null mutations). Additionally, neither Jak3 nor Jak1 were phosphorylated by IL-2 in X-SCID cell lines expressing an array of mutant γ_c proteins, including those with normal extracellular ligand -binding domains. These results indicate that although Jak3 and Jak1 differentially associate with IL-2Rβ andγ_c, activation of the two Janus kinases is linked. In contrast to the results with IL-2R, the IL-4R signaling pathway was partially maintained in X-SCID cells; Jak1 but not Jak3 was activated by IL-4 in all analyzed X-SCID lines. Moreover, downstream signalling was maintained as assessed by activation of Stat6, a member of the signal transducer and activator of transcription (STAT) family of proteins. The data indicate the presence of an IL-4R pathway, independent of γC, which is functional in X-SCID lymphocytes. The redundancy of these two distinct IL-4 receptors has important implications for understanding the pathophysiology and future treatments of X-SCID, as well as the normal function of IL-4.