Journal of Molecular Evolution

, Volume 61, Issue 5, pp 608–619

Gamma Chain Receptor Interleukins: Evidence for Positive Selection Driving the Evolution of Cell-to-Cell Communicators in the Mammalian Immune System



The interleukin-2 receptor (IL-2R) γ chain, or common γ chain (γc), is the hub of a protein interaction network in the mammalia that is central to defense against disease. It is the indispensable subunit of the functional receptor complexes for a group of interleukins known as the γ-chain-dependent interleukins (IL-2, IL-4, -7, -9, -15, and -21). The γc links these proteins through their interaction with it and their competition for its recruitment. The γc-dependent interleukins also interact with each other to either enhance or suppress expression through manipulation of expression of receptor subunits. Given the influence of protein–protein interactions on evolution, such as those documented for many genes including the reproductive proteins of the sperm and egg coat, here we have asked whether there is a common thread in the evolution of these interleukins. Our findings indicate that positive selection has acted by fixing a large number of amino acid replacement mutations in every single one of these interleukins, this adaptive evolution is also observed in a lineage-specific manner. Crucially, however, there does not appear to have ever been an instance of adaptive evolution in the γc chain itself, thereby providing an insight into the evolution of this hub protein. These findings highlight the importance of adaptive evolutionary events in the evolution of this central network in the immune system and suggest underlying causes for differences in defense responses in the mammalia.


Positive selection Interleukins Immune system 


  1. Bubenik J, Krchnak V, Indrova M, Hamsikova E, Jandlova T, Simova J, Kieler J (1987) Localization of a receptor binding site on the IL-2 molecule. Folia Biol (Praha) 33:266–281Google Scholar
  2. Chaiken IM, Williams WV (1996) Identifying structure–function relationships in four-helix bundle cytokines: towards de novo mimetics design. Trends Biotechnol 14:369–375CrossRefPubMedGoogle Scholar
  3. Chang DZ, Wu Z, Ciardelli TL (1996) A point mutation in interleukin–2 that alters ligand internalization. J Biol Chem 271:13349–3355CrossRefPubMedGoogle Scholar
  4. Chou YK, Bourdette DN, Barnes D, Finn TP, Murray S, Unsicker L, Robey I, Whitham RH, Buenafe AC, Allegretta M, Offner H, Vandenbark AA (1999) IL-7 enhances Ag-specific human T cell response by increasing expression of IL-2R alpha and gamma chains. J Neuroimmunol 96:101–111CrossRefPubMedGoogle Scholar
  5. Emes RD, Goodstadt L, Winter EE, Ponting CP (2003) Comparison of the genomes of human and mouse lays the foundation of genome zoology. Hum Mol Genet 12:701–709CrossRefPubMedGoogle Scholar
  6. Felsenstein J (1985) Confidence-limits on phylogenies—an approach using the bootstrap. Evolution 39:783–791Google Scholar
  7. Fukushima K, Hara-Kuge S, Ideo H, Yamashita K (2001) Carbohydrate recognition site of interleukin-2 in relation to cell proliferation. J Biol Chem 276:31202–31208CrossRefPubMedGoogle Scholar
  8. Gilad Y, Man O, Paabo S, Lancet D (2003) Human specific loss of olfactory recpetor genes. Proc Natl Acad Sci USA 100:3324–3327CrossRefPubMedGoogle Scholar
  9. Goh CS, Cohen FE (2002) Co–evolutionary analysis reveals insights into protein–protein interactions. J Mol Biol 324:177–192CrossRefPubMedGoogle Scholar
  10. Goldman N, Yang Z (1994) A codon–based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol 11:725PubMedGoogle Scholar
  11. He YW, Adkins B, Furse RK, Malek TR (1995) Expression and function of the gamma c subunit of the IL-2, IL-4, and IL-7 receptors. Distinct interaction of gamma c in the IL–4 receptor. J Immunol 154:1596–1605PubMedGoogle Scholar
  12. Imbert V, Rezzonico R, Reichenbach P, Nabholz M (2002) Induction of interleukin-2 receptor alpha (IL–2Ralpha) expression by interleukin-2: important role of the interleukin-2 receptor beta chain region between the two Stat5 docking sites. Eur Cytokine Network 13:331–339Google Scholar
  13. Kimura M (1983) The neutral theory of molecular evolution. Cambridge University Press, CambridgeGoogle Scholar
  14. Kneitz B, Herrmann T, Yonehara S, Schimpl A (1995) Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. Eur J Immunol 25:2572–2577PubMedGoogle Scholar
  15. Kruse N, Shen BJ, Arnold S, Tony HP, Muller T, Sebald W (1993) Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation. EMBO J 12:5121–5129PubMedGoogle Scholar
  16. Lenardo MJ (1991) Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 353:858–861CrossRefPubMedGoogle Scholar
  17. Leonard WJ (1999) Fundamental immunology. Lippincott-Raven, PhiladelphiaGoogle Scholar
  18. Leonard WJ, Shores EW, Love PE (1995) Role of the common cytokine receptor gamma chain in cytokine signaling and lymphoid development. Immunol Rev 148:97–114PubMedGoogle Scholar
  19. Messier W, Stewart CB (1997) Episodic adaptive evolution of primate lysozymes. Nature 385:151–154CrossRefPubMedGoogle Scholar
  20. Mestas J, Hughes CCW (2004) Of mice and not men: Differences between mouse and human immunology. J Immunol 172:2731–2738PubMedGoogle Scholar
  21. Morrison BW, Leder P (1992) A receptor binding domain of mouse interleukin-4 defined by a solid-phase binding assay and in vitro mutagenesis. J Biol Chem 267:11957–11963PubMedGoogle Scholar
  22. Nielsen R, Yang ZH (1998) Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148:929–936PubMedGoogle Scholar
  23. Ohta T, (1992) The nearly neutral theory of molecular evolution. Annu Rev Ecol Syst 23:263–286CrossRefGoogle Scholar
  24. Olosz F, Malek TR (2000) Three loops of the common gamma chain ectodomain required for the binding of interleukin-2 and interleukin-7. J Biol Chem 275:30100–30105CrossRefPubMedGoogle Scholar
  25. Olosz F, Malek TR (2002) Structural basis for binding multiple ligands by the common cytokine receptor gamma-chain. J Biol Chem 277:12047–12052CrossRefPubMedGoogle Scholar
  26. Peschon JJ, Morrissey PJ, Grabstein KH, Ramsdell FJ, Maraskovsky E, Gliniak BC, Park LS, Ziegler SF, Williams DE, Ware CB, Meyer JD, Davison BL (1994) Early lymphocyte expansion is severely impaired in interleukin-7 receptor-deficient mice. 180:1955–1960Google Scholar
  27. Pettit DK, Bonnert TP, Eisenman J, Srinivasan S, Paxton R, Beers C, Lynch D, Miller B, Yost J, Grabstein KH, Gombotz WR (1997) Structure–function studies of interleukin 15 using site-specific mutagenesis, polyethylene glycol conjugation, and homology modeling. J Biol Chem 272:2312–2318CrossRefPubMedGoogle Scholar
  28. Ramanathan L, Ingram R, Sullivan L, Greenberg R, Reim R, Trotta PP, Le HV (1993) Immunochemical mapping of domains in human interleukin 4 recognized by neutralizing monoclonal antibodies. Biochemistry 32:3549–3556CrossRefPubMedGoogle Scholar
  29. Raskin N, Jakubowski A, Sizing ID, Olson DL, Kalled SL, Hession CA, Benjamin CD, Baker DP, Burkly LC (1998) Molecular mapping with functional antibodies localizes critical sites on the human IL receptor common gamma (gamma c) chain. J Immunol 161:3474–3483PubMedGoogle Scholar
  30. Robb RJ (1985) Interleukin-2 and its cell-surface receptor. Behring Inst Mitt 77:56–67PubMedGoogle Scholar
  31. Rockman MV, Hahn MW, Soranzo N, Goldstein DB, Wray GA (2003) Positive selection on a human-specific transcription factor binding site regulating IL4 expression. Curr Opin Biol 13:2118–2123Google Scholar
  32. Roessler E, Grant A, Ju G, Tsudo M, Sugamura K, Waldmann TA (1994) Cooperative interactions between the interleukin 2 receptor alpha and beta chains alter the interleukin 2-binding affinity of the receptor subunits. Proc Natl Acad Sci USA 91:3344–3347PubMedGoogle Scholar
  33. Roifman CM, Zhang JY, Chitayat D, Sharfe N (2000) A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Proc Natl Acad Sci USA 96:2803–2807Google Scholar
  34. Rose T, Moreau JL, Eckenberg R, Theze J (2003) Structural analysis and modeling of a synthetic interleukin-2 mimetic and its interleukin-2Rbeta2 receptor. J Biol Chem 278:22868–22876CrossRefPubMedGoogle Scholar
  35. Rudikoff S, Giusti AM, Cook WD, Scharff MD (1982) Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci USA 79:1979–1983PubMedGoogle Scholar
  36. Stewart CB, Schilling JW, Wilson AC (1987) Adaptive evolution in the stomach lysozymes of foregut fermenters. Nature 330:401–404CrossRefPubMedGoogle Scholar
  37. Swofford DL (1998) PAUP*. Phylogenetic Analysis Using Parsimony (*and other methods). Sinauer Associates, Sunderland, MAGoogle Scholar
  38. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedGoogle Scholar
  39. Torgerson DG, Kulathinal RJ, Singh RS (2002) Mammalian sperm proteins are rapidly evolving: evidence of positive selection in functionally diverse genes. Mol Biol Evol 19:1973–1980PubMedGoogle Scholar
  40. Walter MR, Cook WJ, Zhao BG, Cameron RPJ, Ealick SE, Walter RLJ, Reichert P, Nagabhushan TL, Trotta PP, Bugg CE (1992) Crystal structure of recombinant human interleukin-4. J Biol Chem 267:20371–20376PubMedGoogle Scholar
  41. Xue HH, Kovanen PE, Pise–Masison CA, Berg M, Radovich MF, Brady JN, Leonard WJ (2002) IL-2 negatively regulates IL-7 receptor alpha chain expression in activated T lymphocytes. Proc Natl Acad Sci USA 99:13759–13764CrossRefPubMedGoogle Scholar
  42. Yang Z (1998) Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol Biol Evol 15:568–573PubMedGoogle Scholar
  43. Yang Z, Nielsen R (2002) Codon-substitution models for detecting molecular adaptation at individual sites along specific lineages. Mol Biol Evol 19:908–917PubMedGoogle Scholar
  44. Yang Z, Nielsen R, Goldman N, Pedersen AM (2000) Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics 155:431–449PubMedGoogle Scholar
  45. Younger RM, Amadou C, Bethel G, Ehlers A, Fischer Lindahl K, Forbes S, Horton R, Milne S, Mungall A, Trowsdale J, Volz A, Ziegler A, Beck S (2001) Characterization of clustered mhc-linked olfactory receptor genes in human and mouse. Genome Res 11:519–530CrossRefPubMedGoogle Scholar
  46. Zelus D, Robinson-Rechavi M, Delacre M, Auriault C, Laudet V (2000) Fast evolution of interleukin-2 in mammals and positive selection in ruminants. J Mol Evol 51:234–244PubMedGoogle Scholar
  47. Zhang JL, Buehner M, Sebald W (2002) Functional epitope of common gamma chain for interleukin-4 binding. Eur J Biochem 269:1490–1499CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Bioinformatics and Molecular Evolution Laboratory, School of BiotechnologyDublin City UniversityGlasnevinIreland
  2. 2.Bioinformatics and Pharmacogenomics Laboratory, Department of BiologyNational University of Ireland MaynoothMaynoothIreland

Personalised recommendations