The Common γ Chain (γc) Is a Required Signaling Component of the IL-21 Receptor and Supports IL-21-Induced Cell Proliferation via JAK3

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Abstract
The common cytokine receptor γ chain (γc), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, a novel lymphokine (IL-21) and its receptor (IL-21Rα) were described which profoundly affect the growth and activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-Novak, J., et al. (2000) Nature 408, 57−63]. In this report, we show that γc is also a required signaling component of the IL-21 receptor (IL-21R) using the γc-deficient X-linked severe combined immunodeficiency (XSCID) lymphoblastoid cell line JT, and JT cells reconstituted with γc (JT/γc). Moreover, we demonstrate a functional requirement for both γc and the γc-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21Rα (BaF3/IL-21Rα). Retroviral-mediated transduction of wild-type γc into XSCID JT cells restored function to the IL-21R, as shown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation of STAT5, in JT/γc cells as well as BaF3/IL-21Rα and primary splenic B cells. In contrast, IL-21 failed to activate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the γc chain effectively inhibited IL-21-induced growth of BaF3/IL-21Rα cells, supporting a functional role for this molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131 significantly reduced IL-21-induced proliferation of BaF3/IL-21Rα cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the γc chain, and indicate that JAK3 is an essential transducer of γc-dependent survival and/or mitogenic signals induced by this cytokine.