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.

[1]  J. Thèze,et al.  Structural Analysis and Modeling of a Synthetic Interleukin-2 Mimetic and Its Interleukin-2Rβ2 Receptor* , 2003, Journal of Biological Chemistry.

[2]  A. Mungall,et al.  Characterization of clustered MHC-linked olfactory receptor genes in human and mouse. , 2001, Genome research.

[3]  T. Waldmann,et al.  Cooperative interactions between the interleukin 2 receptor alpha and beta chains alter the interleukin 2-binding affinity of the receptor subunits. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[4]  W. Leonard,et al.  Role of the Common Cytokine Receptor γ Chain in Cytokine Signaling and Lymphoid Development , 1995, Immunological reviews.

[5]  K. Holsinger.  The neutral theory of molecular evolution , 2004 .

[6]  R. Nielsen,et al.  Codon-substitution models for detecting molecular adaptation at individual sites along specific lineages. , 2002, Molecular biology and evolution.

[7]  S E Ealick,et al.  Crystal structure of recombinant human interleukin-4. , 1994, The Journal of biological chemistry.

[8]  W. Sebald,et al.  Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation. , 1993, The EMBO journal.

[9]  W. Leonard,et al.  IL-2 negatively regulates IL-7 receptor α chain expression in activated T lymphocytes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  W. Sebald,et al.  Functional epitope of common gamma chain for interleukin-4 binding. , 2002, European journal of biochemistry.

[11]  D. Bourdette,et al.  IL-7 enhances Ag-specific human T cell response by increasing expression of IL-2R α and γ chains , 1999, Journal of Neuroimmunology.

[12]  D. Chitayat,et al.  A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. , 2000, Blood.

[13]  Chern-Sing Goh,et al.  Co-evolutionary analysis reveals insights into protein-protein interactions. , 2002, Journal of molecular biology.

[14]  N. Goldman,et al.  A codon-based model of nucleotide substitution for protein-coding DNA sequences. , 1994, Molecular biology and evolution.

[15]  Allan C. Wilson,et al.  Adaptive evolution in the stomach lysozymes of foregut fermenters , 1987, Nature.

[16]  D. Chitayat,et al.  A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency , 2000 .

[17]  K. Fukushima,et al.  Carbohydrate Recognition Site of Interleukin-2 in Relation to Cell Proliferation* , 2001, The Journal of Biological Chemistry.

[18]  S. Rudikoff,et al.  Single amino acid substitution altering antigen-binding specificity. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. Sullivan,et al.  Immunochemical mapping of domains in human interleukin 4 recognized by neutralizing monoclonal antibodies. , 1993, Biochemistry.

[20]  D. Swofford.  PAUP*: Phylogenetic analysis using parsimony (*and other methods), Version 4.0b10 , 2002 .

[21]  Zining Wu,et al.  A Point Mutation in Interleukin-2 That Alters Ligand Internalization* , 1996, The Journal of Biological Chemistry.

[22]  Dara G Torgerson,et al.  Mammalian sperm proteins are rapidly evolving: evidence of positive selection in functionally diverse genes. , 2002, Molecular biology and evolution.

[23]  N. Goldman,et al.  Codon-substitution models for heterogeneous selection pressure at amino acid sites. , 2000, Genetics.

[24]  Matthew W. Hahn,et al.  Positive Selection on a Human-Specific Transcription Factor Binding Site Regulating IL4 Expression , 2003, Current Biology.

[25]  P. Leder,et al.  A receptor binding domain of mouse interleukin-4 defined by a solid-phase binding assay and in vitro mutagenesis. , 1992, The Journal of biological chemistry.

[26]  I. Chaiken,et al.  Identifying structure-function relationships in four-helix bundle cytokines: towards de novo mimetics design. , 1996, Trends in biotechnology.

[27]  C. Hughes,et al.  Of Mice and Not Men: Differences between Mouse and Human Immunology , 2004, The Journal of Immunology.

[28]  S. Yonehara,et al.  Normal clonal expansion but impaired Fasmediated cell death and anergy induction in interleukin‐2‐deficient mice , 1995, European journal of immunology.

[29]  Richard D Emes,et al.  Comparison of the genomes of human and mouse lays the foundation of genome zoology. , 2003, Human molecular genetics.

[30]  V. Laudet,et al.  Fast Evolution of Interleukin-2 in Mammals and Positive Selection in Ruminants , 2000, Journal of Molecular Evolution.

[31]  W. Sebald,et al.  Functional epitope of common γ chain for interleukin-4 binding , 2002 .

[32]  J. Felsenstein.  CONFIDENCE LIMITS ON PHYLOGENIES: AN APPROACH USING THE BOOTSTRAP , 1985, Evolution; international journal of organic evolution.

[33]  T. Ohta.  THE NEARLY NEUTRAL THEORY OF MOLECULAR EVOLUTION , 1992 .

[34]  T. Malek,et al.  Structural Basis for Binding Multiple Ligands by the Common Cytokine Receptor γ-Chain* , 2002, The Journal of Biological Chemistry.

[35]  D. Baker,et al.  Molecular mapping with functional antibodies localizes critical sites on the human IL receptor common gamma (gamma c) chain. , 1998, Journal of immunology.

[36]  Michael P. Cummings,et al.  PAUP* [Phylogenetic Analysis Using Parsimony (and Other Methods)] , 2004 .

[37]  W. Leonard,et al.  IL-2 negatively regulates IL-7 receptor alpha chain expression in activated T lymphocytes. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Doron Lancet,et al.  Human specific loss of olfactory receptor genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  W. Messier,et al.  Episodic adaptive evolution of primate lysozymes , 1997, Nature.

[40]  V. Imbert,et al.  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. , 2002, European cytokine network.

[41]  R. Nielsen,et al.  Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. , 1998, Genetics.

[42]  M. Lenardo.  Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. , 1991, Nature.

[43]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[44]  C. Ware,et al.  Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice , 1994, The Journal of experimental medicine.

[45]  T. Malek,et al.  Three Loops of the Common γ Chain Ectodomain Required for the Binding of Interleukin-2 and Interleukin-7* , 2000, The Journal of Biological Chemistry.

[46]  R. Paxton,et al.  Structure-Function Studies of Interleukin 15 using Site-specific Mutagenesis, Polyethylene Glycol Conjugation, and Homology Modeling* , 1997, The Journal of Biological Chemistry.

[47]  T. Malek,et al.  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. , 1995, Journal of immunology.

[48]  M. Kimura.  The Neutral Theory of Molecular Evolution: Introduction , 1983 .

[49]  Z. Yang,et al.  Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. , 1998, Molecular biology and evolution.