IL-2 negatively regulates IL-7 receptor α chain expression in activated T lymphocytes

Interleukin (IL)-2 is a type I four-α-helical bundle cytokine that plays vital roles in antigen-mediated proliferation of peripheral blood T cells and also is critical for activation-induced cell death. We now demonstrate that IL-2 potently decreases expression of IL-7 receptor α chain (IL-7Rα) mRNA and protein. The fact that IL-7Rα is a component of the receptors for both IL-7 and thymic stromal lymphopoietin (TSLP) suggests that IL-2 can negatively regulate signals by each of these cytokines. Previously it was known that the IL-2 and IL-7 receptors shared the common cytokine receptor γ chain, γc, which suggested a possible competition between these cytokines for a receptor component. Our findings now suggest a previously unknown type of cross-talk between IL-2 and IL-7 signaling by showing that IL-2 signaling can diminish IL-7Rα expression via a phosphatidylinositol 3-kinase/Akt-dependent mechanism.

[1]  Richard Murray,et al.  IL-7 is critical for homeostatic proliferation and survival of naïve T cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  W. Leonard,et al.  The Basis for IL-2-Induced IL-2 Receptor α Chain Gene Regulation , 2001 .

[3]  D. Largaespada,et al.  Cloning of the Murine Thymic Stromal Lymphopoietin (Tslp) Receptor , 2000, The Journal of experimental medicine.

[4]  Heinz Baumann,et al.  Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin , 2000, Nature Immunology.

[5]  L. Toledo,et al.  Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. , 2000, Structure.

[6]  W. Leonard,et al.  The role of Stat5a and Stat5b in signaling by IL-2 family cytokines , 2000, Oncogene.

[7]  P. Marrack,et al.  Control of homeostasis of CD8+ memory T cells by opposing cytokines. , 2000, Science.

[8]  J. Altman,et al.  Cutting Edge: Increased Expression of Bcl-2 in Antigen-Specific Memory CD8+ T Cells1 , 2000, The Journal of Immunology.

[9]  D. Baltimore,et al.  Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. , 1999, Immunity.

[10]  K. Muegge,et al.  Interleukin-7: physiological roles and mechanisms of action. , 1999, Cytokine & growth factor reviews.

[11]  J. Ihle,et al.  Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. , 1999, Immunity.

[12]  R. Perlmutter,et al.  Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. , 1999, Journal of immunology.

[13]  W. Leonard,et al.  Role of Bcl-2 in alpha beta T cell development in mice deficient in the common cytokine receptor gamma-chain: the requirement for Bcl-2 differs depending on the TCR/MHC affinity. , 1999, Journal of Immunology.

[14]  Steven F. Ziegler,et al.  Defective IL7R expression in T-B+NK + severe combined immunodeficiency , 1998, Nature Genetics.

[15]  W. Leonard,et al.  Functional Cooperation of the Interleukin-2 Receptor β Chain and Jak1 in Phosphatidylinositol 3-Kinase Recruitment and Phosphorylation , 1998, Molecular and Cellular Biology.

[16]  D. Reen,et al.  IL‐7 promotes the survival and maturation but not differentiation of human post‐thymic CD4+ T cells , 1998, European journal of immunology.

[17]  A. Newton,et al.  Regulation of protein kinase C ζ by PI 3-kinase and PDK-1 , 1998, Current Biology.

[18]  C Caux,et al.  The cytokine profile expressed by human dendritic cells is dependent on cell subtype and mode of activation. , 1998, Journal of immunology.

[19]  A. Strasser,et al.  Bcl-2 Can Rescue T Lymphocyte Development in Interleukin-7 Receptor–Deficient Mice but Not in Mutant rag-1 −/− Mice , 1997, Cell.

[20]  I. Weissman,et al.  Bcl-2 Rescues T Lymphopoiesis in Interleukin-7 Receptor–Deficient Mice , 1997, Cell.

[21]  B. Groner,et al.  Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype , 1996, Molecular and cellular biology.

[22]  S. Fesik,et al.  Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  W. Leonard,et al.  Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Hanke,et al.  Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase Inhibitor , 1996, The Journal of Biological Chemistry.

[25]  F. Alt,et al.  Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. , 1995, Immunity.

[26]  H. Griesser,et al.  Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. , 1995, Science.

[27]  Augusto Silva,et al.  The ζ Isoform of Protein Kinase C Controls Interleukin-2-Mediated Proliferation in a Murine T Cell Line: Evidence for an Additional Role of Protein Kinase C ϵ and β , 1995 .

[28]  T. Taniguchi Cytokine signaling through nonreceptor protein tyrosine kinases. , 1995, Science.

[29]  S. Burdach,et al.  Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine , 1995, The Journal of experimental medicine.

[30]  W. Leonard,et al.  The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. , 1995, Immunity.

[31]  R. Abraham,et al.  The Src-family kinase, Fyn, regulates the activation of phosphatidylinositol 3-kinase in an interleukin 2-responsive T cell line , 1994, The Journal of experimental medicine.

[32]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[33]  A. Arcaro,et al.  Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. , 1993, The Biochemical journal.

[34]  A. Feller,et al.  Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene , 1993, Cell.

[35]  J C Reed,et al.  Evidence that protein tyrosine kinase p56-Lck regulates the activity of phosphatidylinositol-3'-kinase in interleukin-2-dependent T-cells. , 1993, The Journal of biological chemistry.

[36]  T. Waldmann,et al.  Interleukin-2, interleukin-15, and their receptors. , 1998, International reviews of immunology.