Abstract
Individuals with certain HLA class I genotypes are highly susceptible to disease after viral infection. Natural killer (NK) cells kill virus-infected cells through a mechanism involving HLA class I receptors. These facts may be connected if an individual's HLA genotype regulates the number and function of NK cells. We have observed that subjects homozygous for the HLA-B/C region of conserved major histocompatibility complex (MHC) extended haplotypes have lower NK cell activity and a significantly lower frequency of CD16+CD56+ NK cells than heterozygotes. The proportion of CD16−CD56+ NK cells was unaffected by zygosity for the HLA-B/C region. We show here that the frequency of CD16+CD158b+, but not CD16−CD158b+ NK cells, was significantly lower (p <0.026) in homozygotes for HLA-Cw7 (NK1 ligand) haplotypes than in heterozygotes. The frequencies of CD16+CD158a+ and CD16−CD158a+ and CD16−CD158a+ or CD16+NKB1+ and CD16−NKB1+ NK cells were not different in these donor groups. These findings suggest that the proportion of NK cells coexpressing CD16 and CD158b, but not CD158a nor NKB1, is influenced by zygosity for the HLA-Cw7 (NK1 ligand) haplotype. Since NK cells are involved in protection from virus infection, a reduced size of a ligand-specific NK subset in individuals homozygous for some HLA-B/C haplotypes may help explain their increased susceptibility to virus-induced diseases.
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REFERENCES
Cohen OJ, Kinter A, Fauci AS: Host factors in the pathogenesis of HIV disease. Immunol Rev 159:31–48, 1997
Hill AV: The immunogenetics of human infectious diseases. Annu Rev Immunol 16:593–617, 1998
Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O'Brien SJ: HLA and HIV-1: Heterozygote advantage and B*35-Cw*4 disadvantage. Science 283:1748–1752, 1999
Jeffery KJM, Siddiqui AA, Bunce M, Lloyd AL, Vine AM, Witkover AD, Izumo S, Usuku K, Welsh KI, Osame M, Bangham CRM: The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J Immunol 165:7278–7284, 2000
Whiteside TL, Herberman RB: Human natural killer cells in health and disease. Biology and therapeutic potential. Clin Immunother 1:56–66, 1994
Bukowski JF, Warner JF, Dennert G, Welsh RM: Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J Exp Med 161:40–52, 1985
Dubey DP, Staunton DE, Azocar J, Stux S, Essex M, Yunis EJ: Natural killer activity against retrovirus infected cells: Dichotomy in NK sensitivity of infected T and B cells. Clin Immunol Immunopathol 23:215–223, 1982
Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP: Natural killer cells in antiviral defense: Function and regulation of innate cytokines. Annu Rev Immunol 17:189–220, 1999
Dubey DP, Staunton DE, Smith BL, Yunis EJ, Sager R: Lysis of Chinese hamster embryo fibroblast mutants by human natural cytotoxic (NK) cells. Proc Natl Acad Sci USA 80:7303–7307, 1983
Ljunggren HG, Kärre K: In search of the “missing self”: MHC molecules and NK recognition. Immunol Today 11:237–244, 1990
Biron CA, Byron KS, Sullivan JL: Severe herpesvirus infection in an adolescent without natural killer cells. N Engl J Med 320:1731–1735, 1989
Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH: The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 136:4480–4486, 1986
Nagler A, Lanier LL, Cwirla S, Phillips JH: Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol 143:3183–3191, 1989
Mandelboim O, Malik P, Davis DM, Jo CH, Boyson JE, Strominger JL: Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc Natl Acad Sci USA 96:5640–5644, 1999
Moretta A, Bottino C, Vitale M, et al: Receptors for HLA class I molecules in human natural killer cells. Annu Rev Immunol 14:619–648, 1996
Lopez-Botet M, Bellon T: Natural killer cell activation and inhibition by receptors for MHC class I. Curr Opin Immunol 11:301–307, 1999
Vales-Gomez M, Reyburn HT, Strominger JL: Interaction between the human NK receptors and their ligands. Critical Rev Immunol 20:223–244, 2000
Lanier LL: On guard-activating NK cell receptors. Nature Immunol 2:23–27, 2000
Carretero M, Cantoni C, Bellon T, et al: The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for class I molecules. Eur J Immunol 27:563–567, 1997
Braud VM, Allan DSJ, O'Callaghan CA, et al: HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391:795–799, 1998
Dubey DP, Alper CA, Mirza NM, Awdeh Z, Yunis EJ: Polymorphic Hh genes in the HLA-B(C) region control natural killer cell frequency and activity. J Exp Med 179:1193–1203, 1994
Alper CA, Awdeh Z, Yunis EJ: Conserved, extended MHC haplotypes. Exp Clin Immunogenet 9:58–71, 1992
Dawkins R, Leelayuwat C, Gaudieri S, Tay G, Hui J, Cattley S, Martinez P, Kulski J: Genomics of the major histocompatibility complex: Haplotypes, duplication, retroviruses and disease. Immunol Rev 167:275–304, 1999
Ray JG, Hare DB, Pedersen PD, Mulally DI (ed): NIAID Manual of Tissue Typing Techniques. US Department of Health, Education, and Welfare, Bethesda, MD, 1976, NIH publication No. 76-545, pp1–210
Bunce M, O'Neill CM, Barnardo MCNM, et al.: Phototyping comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 by PCR with 144 primer mixes utilizing sequence specific primers (PCR-SSP). Tissue Antigens 46:355–367
Sokal RR, Rohlf FJ: Biometry, the Principles and Practice of Statistics in Biology. San Fransisco, WH Freeman, 1969
Frohn C, Schlenke P, Kirchner H: The repertoire of HLA-Cwspecific NK cell receptors CD158 a/b (EB6 and GL183) in individuals with different HLA phenotypes. Immunology 92:567–570, 1997
Gumperz JE, Valiante NM, Parham P, Lanier LL, Tyan D: 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 histocompatibility complex haplotypes. J Exp Med 183:1817–1827, 1996
Bunce M, Barnardo MC, Proctor J, Mash SG, Vilches C, Welsh KL: High resolution HLA-C typing by PCR-SSP. Identification of allele frequencies and linkage equilibrium in 604 unrelated random UK Caucasoid and a comparison with serology (corrected and republished article originally printed in 1996, Tissue Antigens, 48: 680). Tissue Antigens 50:100-111, 1997
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T: Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729, 1999
Jewett A, Bonavida B: MHC-class I antigens regulate both the function and the survival of human peripheral blood NK cells: role of endogenously secreted TNF-α. Clin Immunol 6:19–28, 2000
Naper C, Ryan JC, Kirsch R, Butcher GW, Rolstad B, Vaage JT: Genes in two major histocompatibility complex class I regions control selection, phenotype, and function of a rat Ly49 natural killer cell subset. Eur J Immunol 29:2049–2053, 1999
Karlhofer FM, Hunziker R, Reichlin A, Margulies DH, Yokoyama WM: Host MHC class I molecules modulate in vivo expression of a NK cell receptor. J Immunol 153:2407–2416, 1994
Olsson MY, Kärre K, Sentman CL: Altered phenotype and function of natural killer cells expressing the major histocompatibility complex receptor Ly-49 in mice transgenic for its ligand. Proc Natl Acad Sci USA 92:1649–1653, 1995
Held W, Dorfman JR, Wu M-F, Raulet DH: Major histocompatibility complex class I-dependent skewing of the natural killer cell Ly49 receptor repertoire. Eur J Immunol 26:2286–2292, 1996
Winter CC, Gumperz JE, Parham P, Long EO, Wagtmann N: Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J Immunol 161:571–577, 1998
Vales-Gomez M, Reyburn HT, Erskine RA, Strominger JK: Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. Proc Natl Acad Sci USA 95:14326–14331, 1998
Roth C, Carlyle JR, Takizawa H, Raulet DH: Clonal acquisition of inhibitory receptors on developing NK cells is successively restricted and regulated by stromal class I MHC. Immunity 13:143–153, 2000
Carayol G, Robin C, Bourhis J-H, et al: NK cells differentiated from bone marrow cord blood and peripheral blood stem cells exhibit similar phenotype and functions. Eur J Immunol 28:1991–2002, 1998
Cook JR, Wormstall E, Hornell T, Russell J, Connolly JM, Hansen TH: Quantitation of the cell surface level of Ld resulting in positive versus negative selection of the 2C transgenic T cell receptor in vivo.Immunity 7:233–241, 1997
Blery M, Delon J, Trautmann A, et al: Reconstituted killer cell inhibitory receptors for major histocompatibility complex class I molecules control mast cell activation induced via immunoreceptor tyrosine-based activation motifs. J Biol Chem 272:8989–8994, 1997
Arase N, Arase H, Park SY, Ohno H, Ra C, Saito T: Association of FcR_ is essential for activation signal through NKR-P1 (CD161) in natural killer (NK) cell and NK1.1_T cells. J. Exp Med 186:1957–1963, 1997
Alexander-Miller, MA, Derby MA, Sarin A, Henkart PA, Berzofsky J: Supraoptimal peptide-major histocompatibility complex causes a decrease in Bcl-2 levels and allows tumor necrosis factor-α receptorII-mediated apoptosis of cytotoxic T lymphocytes. J Exp Med 188:131–139, 1998
Flores-Villanueva PO, Yunis EJ, Delgado JC, et al: Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc Natl Acad Sci USA. 98:5140–5145, 2001
Cohen GB, Gandhi RT, Davis MM, Mandelboim O, Chen BK, Stromi Baltimore D: The selective down-regulation of class I major histocompatibility complex proteins by HIV-I protects HIV-infected cells from NK cells. Immunity 10:661–671, 1999
Bruunsgaard H, Pederson C, Skinhoj P, Pederson BK: Clinical progression of HIV infection: Role of NK cells. Scand J Immunol 46:91–95, 1997
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Husain, Z., Levitan, E., Larsen, C.E. et al. HLA-Cw7 Zygosity Affects the Size of a Subset of CD158b+ Natural Killer Cells. J Clin Immunol 22, 28–36 (2002). https://doi.org/10.1023/A:1014204519468
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DOI: https://doi.org/10.1023/A:1014204519468