The common γ chain (γc) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3

The common cytokine receptor gamma chain (gammac), 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-21Ralpha) 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 gammac is also a required signaling component of the IL-21 receptor (IL-21R) using the gammac-deficient X-linked severe combined immunodeficiency (XSCID) lymphoblastoid cell line JT, and JT cells reconstituted with gammac (JT/gammac). Moreover, we demonstrate a functional requirement for both gammac and the ye-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21Ralpha (BaF3/IL-21Ralpha). Retroviral-mediated transduction of wild-type gammac 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/gammac cells as well as BaF3/IL-21Ralpha 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 gammac chain effectively inhibited IL-21-induced growth of BaF3/IL-21Ralpha 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-21Ralpha cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the gammac chain, and indicate that JAK3 is an essential transducer of gammac-dependent survival and/or mitogenic signals induced by this cytokine.