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Sequence Motifs in IL-4R Mediating Cell-Cycle Progression of Primary Lymphocytes¹

Linda M. Stephenson^2,*, Do-Sim Park^*, Ana L. Mora^3,*, Shreevrat Goenka^* and Mark Boothby^4,

^* Department of Microbiology and Immunology and Department of Medicine (Rheumatology), Vanderbilt University Medical School, Nashville, TN 37232

IL-4 signaling through the IL-4R chain regulates the development and proliferation of the Th2 lineage of effector CD4⁺ T cells. Analyses of the IL-4R in factor-dependent cell lines led to the development of two apparently conflicting models of the primary structural determinants of IL-4R-mediated proliferative signaling. In one model, proliferation was dependent on the first conserved tyrosine in the cytoplasmic tail (Y1), while in the second, proliferation was independent of cytoplasmic tyrosines. We found that in activated primary T cells, mutation of only the Y1 residue resulted in a modest decrease in IL-4-induced S phase entry, a further decrease in cell-cycle completion, and a complete failure of IL-4 to induce p70S6 kinase phosphorylation. Consistent with a role for the PI3K/mammalian target of rapamycin pathway in mediating cytokine acceleration of G₂/M transit, pretreatment of activated T cells with rapamycin resulted in only a modest decrease in IL-4-induced S phase entry, but a total block of cell-cycle completion. Strikingly, IL-4R chains that lacked all cytoplasmic tyrosines were competent to signal for STAT5 phosphorylation, mediated efficient S phase entry, and promoted cell-cycle progression. The ability of tyrosine-deficient IL-4Rs to mediate proliferative signaling and STAT phosphorylation was absolutely dependent on the presence of an intact ID-1 region. These findings show that IL-4R lacking cytoplasmic tyrosine residues is competent to induce ID-1-dependent proliferation, and indicate that IL-4 can promote G₂/M progression via activation of the mammalian target of rapamycin pathway initiated at the Y1 residue.

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