OLIGOMERIZATION OF IL-2Rα

Abstract Interleukin (IL) 2 receptor subunit alpha (IL-2Rα) increases the affinity of the IL-2 receptor complex while hetero-association of IL-2Rβ and γ c chains initiates a proliferative signal. We show here that IL-2Rα is necessary for receptor clustering required for augmentation of IL-2 signalling. Cells expressing chimeras incorporating the extracellular domain of IL-2Rα demonstrated IL-2 independent homo-association of the IL-2Rα chimera. Singly or co-transfected IL-2Rβ and γ c chimeras showed no spontaneous or IL-2-inducible oligomerization. Co-transfection of IL-2Rα and IL-2Rβ (±γ c ) chimeras diminished spontaneous IL-2Rα chimera oligomerization and permitted IL-2-inducible hetero-oligomerization of receptor components. Homo-association of IL-2Rα was also demonstrated by fluorescence resonance energy transfer (FRET). The spontaneous homo-oligomerization property of IL-2Rα required the membrane proximal region of the receptor (exon 6) by deletion analysis; the IL-2 inducible oligomerization property of IL-2Rα required the second “sushi” domain (exon 4). This work provides insight into the mechanics of this complex receptor system and to other receptor complexes in the immune system that send signals by clustering receptor subunits.

[1]  T. Waldmann,et al.  IL-2Rα on One Cell Can Present IL-2 to IL-2Rβ/γc on Another Cell to Augment IL-2 Signaling , 1998, The Journal of Immunology.

[2]  T. Waldmann,et al.  Preassembly of interleukin 2 (IL-2) receptor subunits on resting Kit 225 K6 T cells and their modulation by IL-2, IL-7, and IL-15: a fluorescence resonance energy transfer study. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  E. Whitehorn,et al.  Ligand binding kinetics of IL-2 and IL-15 to heteromers formed by extracellular domains of the three IL-2 receptor subunits. , 1995, International immunology.

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

[5]  R. Rees,et al.  Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

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

[7]  E. Liu,et al.  Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells , 1994, Nature.

[8]  J. Johnston,et al.  Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2 , 1994, Nature.

[9]  Kendall A. Smith,et al.  Interleukin 2 receptor gamma chain expression on resting and activated lymphoid cells , 1994, The Journal of experimental medicine.

[10]  M. Erdos,et al.  Heterodimerization of the IL-2 receptor β- and γ-chain cytoplasmic domains is required for signalling , 1994, Nature.

[11]  B. Nelson,et al.  Cytoplasmic domains of the interleukin-2 receptor β and γ chains mediate the signal for T-cell proliferation , 1994, Nature.

[12]  R. Zinkernagel,et al.  Immune responses in interleukin-2-deficient mice. , 1993, Science.

[13]  S. Schreiber,et al.  Controlling signal transduction with synthetic ligands. , 1993, Science.

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

[15]  T. Taniguchi,et al.  The IL-2 IL-2 receptor system: A current overview , 1993, Cell.

[16]  T. Taniguchi,et al.  The interleukin-2 receptors: insights into a complex signalling mechanism. , 1992, Biochimica et biophysica acta.

[17]  N. Tanaka,et al.  Cloning of the gamma chain of the human IL-2 receptor. , 1992, Science.

[18]  J. Thèze,et al.  Molecular area involved in the in-vitro dimerization of the murine p55 IL-2 receptor. , 1992, Cytokine.

[19]  T. Waldmann,et al.  The interleukin 2 receptor (IL-2R): the IL-2R alpha subunit alters the function of the IL-2R beta subunit to enhance IL-2 binding and signaling by mechanisms that do not require binding of IL-2 to IL-2R alpha subunit. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Amiot,et al.  Sequence requirements for induction of cytolysis by the T cell antigen Fc receptor ζ chain , 1992, Cell.

[21]  R. Klausner,et al.  T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Arthur Weiss,et al.  The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways , 1991, Cell.

[23]  T. Waldmann,et al.  The interleukin-2 receptor. , 1991, The Journal of biological chemistry.

[24]  J. Soulillou,et al.  Biochemical study of a recombinant soluble interleukin-2 receptor. Evidence for a homodimeric structure. , 1990, The Journal of biological chemistry.

[25]  T. Taniguchi,et al.  Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. , 1989, Science.

[26]  M. Neeper,et al.  Structure-function relationships for the interleukin 2 receptor: location of ligand and antibody binding sites on the Tac receptor chain by mutational analysis. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Korner,et al.  Characterization of the soluble murine IL-2R and estimation of its affinity for IL-2. , 1988, Journal of immunology.

[28]  G. Crabtree,et al.  Molecular cloning and expression of cDNAs for the human interleukin-2 receptor , 1984, Nature.

[29]  T. Honjo,et al.  Molecular cloning of cDNA encoding human interleukin-2 receptor , 1984, Nature.

[30]  N. Tanaka,et al.  The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. , 1996, Annual review of immunology.

[31]  P. Williamson,et al.  Interleukin-2 and the Interleukin-2 Receptor Complex , 1994 .

[32]  T. Taniguchi,et al.  The IL-2 receptor complex: its structure, function, and target genes. , 1993, Annual review of immunology.

[33]  C. March,et al.  Cloning, sequence and expression of human interleukin-2 receptor , 1984, Nature.