Genetic Control of Variegated KIR Gene Expression: Polymorphisms of the Bi-Directional KIR3DL1 Promoter Are Associated with Distinct Frequencies of Gene Expression

Natural killer (NK) cells play an important role in the detection and elimination of tumors and virus-infected cells by the innate immune system. Human NK cells use cell surface receptors (KIR) for class I MHC to sense alterations of class I on potential target cells. Individual NK cells only express a subset of the available KIR genes, generating specialized NK cells that can specifically detect alteration of a particular class I molecule or group of molecules. The probabilistic behavior of human KIR bi-directional promoters is proposed to control the frequency of expression of these variegated genes. Analysis of a panel of donors has revealed the presence of several functionally relevant promoter polymorphisms clustered mainly in the inhibitory KIR family members, especially the KIR3DL1 alleles. We demonstrate for the first time that promoter polymorphisms affecting the strength of competing sense and antisense promoters largely explain the differential frequency of expression of KIR3DL1 allotypes on NK cells. KIR3DL1/S1 subtypes have distinct biological activity and coding region variants of the KIR3DL1/S1 gene strongly influence pathogenesis of HIV/AIDS and other human diseases. We propose that the polymorphisms shown in this study to regulate the frequency of KIR3DL1/S1 subtype expression on NK cells contribute substantially to the phenotypic variation across allotypes with respect to disease resistance.

[1]  Smita Kulkarni,et al.  The Yin and Yang of HLA and KIR in human disease. , 2008, Seminars in immunology.

[2]  Li Yu,et al.  E2F1 contributes to the transcriptional activation of the KIR3DL1 gene. , 2008, Biochemical and biophysical research communications.

[3]  M. Altfeld,et al.  Novel KIR3DL1 Alleles and Their Expression Levels on NK Cells: Convergent Evolution of KIR3DL1 Phenotype Variation?12 , 2008, The Journal of Immunology.

[4]  M. Altfeld,et al.  Detection of KIR3DS1 on the Cell Surface of Peripheral Blood NK Cells Facilitates Identification of a Novel Null Allele and Assessment of KIR3DS1 Expression during HIV-1 Infection12 , 2007, The Journal of Immunology.

[5]  Amalio Telenti,et al.  Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1 , 2007, Nature Genetics.

[6]  H. Aguilar,et al.  Human KIR2DL5 Is an Inhibitory Receptor Expressed on the Surface of NK and T Lymphocyte Subsets1 , 2007, The Journal of Immunology.

[7]  S. Anderson,et al.  Identification of distal KIR promoters and transcripts , 2007, Genes and Immunity.

[8]  G. Davies,et al.  Identification of bidirectional promoters in the human KIR genes , 2007, Genes and Immunity.

[9]  D. Nixon,et al.  Cutting Edge: KIR3DS1, a Gene Implicated in Resistance to Progression to AIDS, Encodes a DAP12-Associated Receptor Expressed on NK Cells That Triggers NK Cell Activation1 , 2007, The Journal of Immunology.

[10]  P. Parham,et al.  Functional Polymorphism of the KIR3DL1/S1 Receptor on Human NK Cells1 , 2007, The Journal of Immunology.

[11]  M. Carrington,et al.  Cutting Edge: Allele-Specific and Peptide-Dependent Interactions between KIR3DL1 and HLA-A and HLA-B12 , 2007, The Journal of Immunology.

[12]  P. Parham Taking license with natural killer cell maturation and repertoire development , 2006, Immunological reviews.

[13]  S. Anderson,et al.  Regulation of class I major histocompatibility complex receptor expression in natural killer cells: one promoter is not enough! , 2006, Immunological reviews.

[14]  P. Parham,et al.  Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function , 2006, The Journal of experimental medicine.

[15]  D. Mager,et al.  Evidence for Epigenetic Maintenance of Ly49a Monoallelic Gene Expression1 , 2006, The Journal of Immunology.

[16]  C. Lutz,et al.  Epigenetic Control of Highly Homologous Killer Ig-Like Receptor Gene Alleles1 , 2005, The Journal of Immunology.

[17]  B. Shykind Regulation of odorant receptors: one allele at a time. , 2005, Human molecular genetics.

[18]  J. Trowsdale,et al.  Structural and functional differences between the promoters of independently expressed killer cell Ig‐like receptors , 2005, European journal of immunology.

[19]  L. Lanier,et al.  Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell–mediated innate resistance to cytomegalovirus infection , 2005, Nature Genetics.

[20]  P. Parham MHC class I molecules and kirs in human history, health and survival , 2005, Nature Reviews Immunology.

[21]  L. Moretta,et al.  Killer immunoglobulin-like receptors. , 2004, Current opinion in immunology.

[22]  E. Romeo,et al.  Isolation of a novel KIR2DL3-specific mAb: comparative analysis of the surface distribution and function of KIR2DL2, KIR2DL3 and KIR2DS2. , 2004, International immunology.

[23]  Salim I. Khakoo,et al.  HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection , 2004, Science.

[24]  Y. Bergman,et al.  Monoallelic gene expression: a repertoire of recurrent themes , 2004, Immunological reviews.

[25]  S. Lockett,et al.  Identification of probabilistic transcriptional switches in the Ly49 gene cluster: a eukaryotic mechanism for selective gene activation. , 2004, Immunity.

[26]  D. Cado,et al.  Genomic Ly49A Transgenes: Basis of Variegated Ly49A Gene Expression and Identification of a Critical Regulatory Element1 , 2004, The Journal of Immunology.

[27]  P. Parham,et al.  The Protein Made from a Common Allele of KIR3DL1 (3DL1*004) Is Poorly Expressed at Cell Surfaces due to Substitution at Positions 86 in Ig Domain 0 and 182 in Ig Domain 1 1 , 2003, The Journal of Immunology.

[28]  B. Plougastel,et al.  Immune functions encoded by the natural killer gene complex , 2003, Nature Reviews Immunology.

[29]  Michael J. Wilson,et al.  DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells , 2003, The Journal of experimental medicine.

[30]  H. Trompeter,et al.  Crucial Role of DNA Methylation in Determination of Clonally Distributed Killer Cell Ig-like Receptor Expression Patterns in NK Cells1 , 2002, The Journal of Immunology.

[31]  Keith Hoots,et al.  Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS , 2002, Nature Genetics.

[32]  L. Lanier,et al.  Direct Recognition of Cytomegalovirus by Activating and Inhibitory NK Cell Receptors , 2002, Science.

[33]  William H. Carr,et al.  Different NK Cell Surface Phenotypes Defined by the DX9 Antibody Are Due to KIR3DL1 Gene Polymorphism1 , 2001, The Journal of Immunology.

[34]  W. Yokoyama,et al.  Nonstochastic Coexpression of Activation Receptors on Murine Natural Killer Cells , 2000, The Journal of experimental medicine.

[35]  W. Held,et al.  An allele‐specific, stochastic gene expression process controls the expression of multiple Ly49family genes and generates a diverse, MHC‐specific NK cell receptor repertoire , 1998, European journal of immunology.

[36]  P Parham,et al.  Human diversity in killer cell inhibitory receptor genes. , 1997, Immunity.

[37]  P Parham,et al.  Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. , 1997, Immunity.

[38]  P. Parham,et al.  Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype , 1996, The Journal of experimental medicine.

[39]  P. Parham,et al.  NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules , 1994, The Journal of experimental medicine.

[40]  E. Ciccone,et al.  Identification of four subsets of human CD3-CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition , 1990, The Journal of experimental medicine.

[41]  G. Trinchieri,et al.  Biology of Natural Killer Cells , 1989, Advances in Immunology.

[42]  M. Carrington,et al.  KIR locus polymorphisms: genotyping and disease association analysis. , 2008, Methods in molecular biology.

[43]  M. Carrington,et al.  KIR locus polymorphisms: genotyping and disease association analysis. , 2008, Methods in molecular biology.

[44]  Lewis L Lanier,et al.  NK cell recognition. , 2005, Annual review of immunology.

[45]  R. Vance,et al.  Regulation of the natural killer cell receptor repertoire. , 2001, Annual review of immunology.

[46]  P. Parham,et al.  Genetic control of human NK cell repertoire , 2001 .