, Volume 70, Issue 9, pp 599–611 | Cite as

Two class I genes of the chicken MHC have different functions: BF1 is recognized by NK cells while BF2 is recognized by CTLs

  • Taejoong KimEmail author
  • Henry D. HuntEmail author
  • Mark S. Parcells
  • Vicky van Santen
  • Sandra J. Ewald
Original Article


The function of the chicken’s major histocompatibility complex (MHC or B complex) class I major (BF2) and minor (BF1) glycoproteins is compared for their expression, ability to present viral antigens to cytotoxic T lymphocytes (CTLs), and interaction with natural killer (NK) cells. MHC-restricted CTLs recognized virus antigen in the context of the BF2*21 major glycoprotein but not the BF1*21 minor glycoprotein. Marek’s disease virus (MDV), a large DNA virus known to reduce the cell surface expression of class I glycoprotein, reduced the expression of BF2 glycoprotein while BF1glycoprotein expressions are remained as no change or slight increase. In addition, the expression of BF1*21 class I glycoprotein protected target cells from NK cell lysis while the expression of the BF2*21 class I glycoprotein enhanced NK cell lysis of target cells. Therefore, BF1 and BF2 provide two different cellular immune functions; BF1 negatively regulates the NK cell killing activity and BF2 restricts the antigen specific CTL immune response.


Chicken MHC Antigen presentation/processing NK cells Cytotoxic T cells 


B complex

(chicken MHC-B)


(chicken MHC class I)


(avian leukosis virus)


(Marek’s disease virus)


(Avian Disease and Oncology Laboratory)



We would like to acknowledge Dr. Terry Lemme and Dr. Noah Koller for excellent technical assistance. The authors would like to extend many thanks to Dr. Jim Kaufman for helpful review of this manuscript.

Compliance with ethical standards


Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture.


  1. Afanassieff M, Goto RM, Ha J, Sherman MA, Zhong L, Auffray C, Coudert F, Zoorob R, Miller MM (2001) At least one class I gene in restriction fragment pattern-Y (Rfp-Y), the second MHC gene cluster in the chicken, is transcribed, polymorphic, and shows divergent specialization in antigen binding region. J Immunol 166(5):3324–3333CrossRefPubMedGoogle Scholar
  2. Bacon LD, Rose NR (1979) Influence of major histocompatibility haplotype on autoimmune disease varies in different inbred families of chickens. Proc Natl Acad Sci U S A 76(3):1435–1437CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bacon LD, Witter RL (1994) B haplotype influence on the relative efficacy of Marek’s disease vaccines in commercial chickens. Poult Sci 73(4):481–487CrossRefPubMedGoogle Scholar
  4. Bacon LD, Polley CR, Cole RK, Rose NR (1981) Genetic influences on spontaneous autoimmune thyroiditis in (CS X OS)F2 chickens. Immunogenetics 12(3–4):339–349CrossRefPubMedGoogle Scholar
  5. Bacon LD, Hunt HD, Cheng HH (2000) A review of the development of chicken lines to resolve genes determining resistance to diseases. Poult Sci 79(8):1082–1093CrossRefPubMedGoogle Scholar
  6. Bacon LD, Hunt HD, Cheng HH (2001) Genetic resistance to Marek’s disease. Curr Top Microbiol Immunol 255:121–141PubMedGoogle Scholar
  7. Boyington JC, Sun PD (2002) A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. Mol Immunol 38(14):1008–1021CrossRefGoogle Scholar
  8. Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD (2000) Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405(6786):537–543. CrossRefPubMedGoogle Scholar
  9. Briles WE, Briles RW, Taffs RE, Stone HA (1983) Resistance to a malignant lymphoma in chickens is mapped to subregion of major histocompatibility (B) complex. Science 219(4587):977–979CrossRefPubMedGoogle Scholar
  10. Briles WE, Goto RM, Auffray C, Miller MM (1993) A polymorphic system related to but genetically independent of the chicken major histocompatibility complex. Immunogenetics 37(6):408–414CrossRefPubMedGoogle Scholar
  11. Chappell PE, Meziane EK, Harrison M, Magiera L, Herman C, Mears L, Wrobel AG, Durant C, Nielsen LL, Buus S, Ternette N, Mwangi W, Butter C, Nair V, Ahyee T, Duggleby R, Madrigal A, Roversi P, Lea SM, Kaufman J (2015) Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding. eLife 4:e05345CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chiang HI, Zhou H, Raudsepp T, Jesudhasan PR, Zhu JJ (2007) Chicken CD69 and CD94/NKG2-like genes in a chromosomal region syntenic to mammalian natural killer gene complex. Immunogenetics 59(7):603–611. CrossRefPubMedGoogle Scholar
  13. Cohen GB, Gandhi RT, Davis DM, Mandelboim O, Chen BK, Strominger JL, Baltimore D (1999) The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10(6):661–671CrossRefPubMedGoogle Scholar
  14. Colonna M, Borsellino G, Falco M, Ferrara GB, Strominger JL (1993) HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proc Natl Acad Sci U S A 90(24):12000–12004CrossRefPubMedPubMedCentralGoogle Scholar
  15. Crittenden LB, Briles WE, Stone HA (1970) Susceptibility to an avian leukosis-sarcoma virus: close association with an erythrocyte isoantigen. Science 169(952):1324–1325CrossRefPubMedGoogle Scholar
  16. Dalgaard TS, Vitved L, Skjodt K, Thomsen B, Labouriau R, Jensen KH, Juul-Madsen HR (2005) Molecular characterization of major histocompatibility complex class I (B-F) mRNA variants from chickens differing in resistance to Marek’s disease. Scand J Immunol 62(3):259–270CrossRefPubMedGoogle Scholar
  17. Dennis G Jr, Kubagawa H, Cooper MD (2000) Paired Ig-like receptor homologs in birds and mammals share a common ancestor with mammalian Fc receptors. Proc Natl Acad Sci U S A 97(24):13245–13250CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dienglewicz RL, Parcells MS (1999) Establishment of a lymphoblastoid cell line using a mutant MDV containing a green fluorescent protein expression cassette. Acta Virol 43(2–3):106–112PubMedGoogle Scholar
  19. Dunon D, Salomonsen J, Skjodt K, Kaufman J, Imhof BA (1990) Ontogenic appearance of MHC class I (B-F) antigens during chicken embryogenesis. Dev Immunol 1(2):127–135CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ewald SJ, Livant EJ (2004) Distinctive polymorphism of chicken B-FI (major histocompatibility complex class I) molecules. Poult Sci 83(4):600–605CrossRefPubMedGoogle Scholar
  21. Faridi RM, Agrawal S (2011) Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Hum Reprod 26(2):491–491CrossRefPubMedGoogle Scholar
  22. Fulton JE, Thacker EL, Bacon LD, Hunt HD (1995) Functional analysis of avian class I (BFIV) glycoproteins by epitope tagging and mutagenesis in vitro. Eur J Immunol 25(7):2069–2076CrossRefPubMedGoogle Scholar
  23. Fulton JE, Hunt HD, Bacon LD (2001) Chicken major histocompatibility complex class I definition using antisera induced by cloned class I sequences. Poult Sci 80(11):1554–1561CrossRefPubMedGoogle Scholar
  24. Gobel TW, Chen CL, Shrimpf J, Grossi CE, Bernot A, Bucy RP, Auffray C, Cooper MD (1994) Characterization of avian natural killer cells and their intracellular CD3 protein complex. Eur J Immunol 24(7):1685–1691CrossRefPubMedGoogle Scholar
  25. Gobel TW, Kaspers B, Stangassinger M (2001) NK and T cells constitute two major, functionally distinct intestinal epithelial lymphocyte subsets in the chicken. Int Immunol 13(6):757–762CrossRefPubMedGoogle Scholar
  26. Goto RM, Wang Y, Taylor RL, Wakenell PS, Hosomichi K, Shiina T, Blackmore CS, Briles WE, Miller MM (2009) BG1 has a major role in MHC-linked resistance to malignant lymphoma in the chicken. Proc Natl Acad Sci U S A 106(39):16740–16745CrossRefPubMedPubMedCentralGoogle Scholar
  27. Guillemot F, Billault A, Pourquie O, Behar G, Chausse AM, Zoorob R, Kreibich G, Auffray C (1988) A molecular map of the chicken major histocompatibility complex: the class II beta genes are closely linked to the class I genes and the nucleolar organizer. EMBO J 7(9):2775–2785PubMedPubMedCentralCrossRefGoogle Scholar
  28. Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR (1989) Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 77(1):51–59CrossRefPubMedGoogle Scholar
  29. Hofmann A, Plachy J, Hunt L, Kaufman J, Hala K (2003) v-src oncogene-specific carboxy-terminal peptide is immunoprotective against Rous sarcoma growth in chickens with MHC class I allele B-F12. Vaccine 21(32):4694–4699CrossRefPubMedGoogle Scholar
  30. Horton RM, Hunt HD, Ho SN, Pullen JK, Pease LR (1989) Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. Gene 77(1):61–68CrossRefPubMedGoogle Scholar
  31. Hughes SH, Greenhouse JJ, Petropoulos CJ, Sutrave P (1987) Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors. J Virol 61(10):3004–3012PubMedPubMedCentralGoogle Scholar
  32. Hunt HD, Fulton JE (1998) Analysis of polymorphisms in the major expressed class I locus (B-FIV) of the chicken. Immunogenetics 47(6):456–467CrossRefPubMedGoogle Scholar
  33. Hunt HD, Lupiani B, Miller MM, Gimeno I, Lee LF, Parcells MS (2001) Marek’s disease virus down-regulates surface expression of MHC (B complex) class I (BF) glycoproteins during active but not latent infection of chicken cells. Virology 282(1):198–205CrossRefPubMedGoogle Scholar
  34. Hunt HD, Goto RM, Foster DN, Bacon LD, Miller MM (2006) At least one YMHCI molecule in the chicken is alloimmunogenic and dynamically expressed on spleen cells during development. Immunogenetics 58(4):297–307CrossRefPubMedGoogle Scholar
  35. Igarashi T, Wynberg J, Srinivasan R, Becknell B, McCoy JP, Takahashi Y et al (2004) Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells. Bloods 104(1):170–177CrossRefGoogle Scholar
  36. Kaufman J (2015) Co-evolution with chicken class I genes. Immunol Rev 267:56–71CrossRefPubMedGoogle Scholar
  37. Kaufman J, Volk H, Wallny HJ (1995) A “minimal essential Mhc” and an “unrecognized Mhc”: two extremes in selection for polymorphism. Immunol Rev 143:63–88CrossRefPubMedGoogle Scholar
  38. Kaufman J, Milne S, Gobel TW, Walker BA, Jacob JP, Auffray C, Zoorob R, Beck S (1999) The chicken B locus is a minimal essential major histocompatibility complex. Nature 401(6756):923–925CrossRefPubMedGoogle Scholar
  39. Koch M, Camp S, Collen T, Avila D, Salomonsen J, Wallny HJ, van Hateren A, Hunt L, Jacob JP, Johnston F, Marston DA, Shaw I, Dunbar PR, Cerundolo V, Jones EY, Kaufman J (2007) Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide bindingl. Immunity 27:885–899CrossRefPubMedGoogle Scholar
  40. Kubota A, Kubota S, Farrell HE, Davis-Poynter N, Takei F (1999) Inhibition of NK cells by murine CMV-encoded class I MHC homologue m144. Cell Immunol 191(2):145–151CrossRefPubMedGoogle Scholar
  41. Laun K, Coggill P, Palmer S, Sims S, Ning Z, Ragoussis J, Volpi E, Wilson N, Beck S, Ziegler A, Volz A (2006) The leukocyte receptor complex in chicken is characterized by massive expansion and diversification of immunoglobulin-like loci. PLoS Genet 2(5):e73CrossRefPubMedPubMedCentralGoogle Scholar
  42. Livant EJ, Zheng D, Johnson LW, Shi W, Ewald SJ (2001) Three new MHC haplotypes in broiler breeder chickens. Anim Genet 32(3):123–131CrossRefPubMedGoogle Scholar
  43. Livant EJ, Brigati JR, Ewald SJ (2004) Diversity and locus specificity of chicken MHC B class I sequences. Anim Genet 35(1):18–27CrossRefPubMedGoogle Scholar
  44. Mandelboim O, Reyburn HT, Vales-Gomez M, Pazmany I, Colonna M, Borsellino G et al (1996) Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. J Exp Med 184(3):913–922CrossRefPubMedGoogle Scholar
  45. Miller MM, Goto R, Bernot A, Zoorob R, Auffray C, Bumstead N, Briles WE (1994) Two Mhc class I and two Mhc class II genes map to the chicken Rfp-Y system outside the B complex. Proc Natl Acad Sci U S A 91(10):4397–4401CrossRefPubMedPubMedCentralGoogle Scholar
  46. Miller MM, Bacon LD, Hala K, Hunt HD, Ewald SJ, Kaufman J, Zoorob R, Briles WE (2004) 2004 nomenclature for the chicken major histocompatibility (B and Y) complex. Immunogenetics 56:261–279PubMedGoogle Scholar
  47. Niikura M, Kim T, Hunt HD, Burnside J, Morgan RW, Dodgson JB, Cheng H (2007) Marek’s disease virus up-regulates major histocompatibility complex class II cell surface expression in infected cells. Virology 359(1):212–219CrossRefPubMedGoogle Scholar
  48. Nikolaidis N, Klein J, Nei M (2005) Origin and evolution of the Ig-like domains present in mammalian leukocyte receptors: insights from chicken, frog, and fish homologues. Immunogenetics 57(1–2):151–157. CrossRefPubMedPubMedCentralGoogle Scholar
  49. O’Neill AM, Livant EJ, Ewald SJ (2009) The chicken BF1 (classical MHC class I) gene shows evidence of selection for diversity in expression and in promoter and signal peptide regions. Immunogenetics 61:289–302CrossRefPubMedGoogle Scholar
  50. O'Callaghan CA, Bell JI (1998) Structure and function of the human MHC class Ib molecules HLA-E, HLA-F and HLA-G. Immunol Rev 163:129–138CrossRefPubMedGoogle Scholar
  51. Okazaki W, Witter RL, Romero C, Nazerian K, Sharma JM, Fadly AM, Ewert D (1980) Induction of lymphoid leukosis transplantable tumours and the establishment of lymphoblastoid cell lines. Avian Pathology 9:311–329CrossRefPubMedGoogle Scholar
  52. Omar AR, Schat KA, Lee LF, Hunt HD (1998) Cytotoxic T lymphocyte response in chickens immunized with a recombinant fowlpox virus expressing Marek’s disease herpesvirus glycoprotein B. Vet Immunol Immunopathol 62(1):73–82CrossRefPubMedGoogle Scholar
  53. Parker MA, Schierman LW (1987) Evidence for MHC gene control of lesion severity in experimental allergic encephalomyelitis of chickens. Prog Clin Biol Res 238:189–198PubMedGoogle Scholar
  54. Petropoulos CJ, Hughes SH (1991) Replication-competent retrovirus vectors for the transfer and expression of gene cassettes in avian cells. J Virol 65(7):3728–3737PubMedPubMedCentralGoogle Scholar
  55. Pharr GT, Gwynn AV, Bacon LD (1996) Histocompatibility antigen(s) linked to Rfp-Y (Mhc-like) genes in the chicken. Immunogenetics 45(1):52–58CrossRefPubMedGoogle Scholar
  56. Prigge JT, Majerciak V, Hunt HD, Dienglewicz RL, Parcells MS (2004) Construction and characterization of Marek’s disease viruses having green fluorescent protein expression tied directly or indirectly to phosphoprotein 38 expression. Avian Dis 48(3):471–487CrossRefPubMedGoogle Scholar
  57. Ramsuran V, Naranbhai V, Horowitz A, Qi Y, Martin MP, Yuki Y, Gao X, Walker-Sperling V, Del Prete GA, Schneider DK, Lifson JD, Fellay J, Deeks SG, Martin JN, Goedert JJ, Wolinsky SM, Michael NL, Kirk GD, Buchninder S, Haas D, Ndungu T, Goulder P, Parham P, Walker BD, Carlson JM, Carrington M (2018) Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells. Science 359:86–90CrossRefPubMedPubMedCentralGoogle Scholar
  58. Rogers S, Shaw I, Ross N, Nair V, Rothwell L, Kaufman J, Kaiser P (2003) Analysis of part of the chicken Rfp-Y region reveals two novel lectin genes, the first complete genomic sequence of a class I alpha-chain gene, a truncated class II beta-chain gene, and a large CR1 repeat. Immunogenetics 55(2):100–108PubMedGoogle Scholar
  59. Rogers SL, Gobel TW, Viertiboeck BC, Milne S, Beck S, Kaufman J (2005) Characterization of the chicken C-type lectine-like receptors B-NK and B-lec suggests that the NK complex and the MHC share a common ancestral region. J Immunol 174(6):3475–3483CrossRefPubMedGoogle Scholar
  60. Romagnani C, Pietra G, Falco M, Mazzarino P, Moretta L, Mingari MC (2004) HLA-E-restricted recognition of human cytomegalovirus by a subset of cytolytic T lymphocytes. Hum Immunol 65(5):437–445CrossRefPubMedGoogle Scholar
  61. Saper MA, Bjorkman PJ, Wiley DC (1991) Refined structire of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution. J Mol Biol 219(2):277–319Google Scholar
  62. Schierman LW, Nordskog AW (1961) Relationship of blood type to histocompatibility in chickens. Science 134:1008–1009CrossRefPubMedGoogle Scholar
  63. Schierman LW, Nordskog AW (1963) Influence of the B bloodgroup-histocompatibility locus in chickens on a graft-versus-host reaction. Nature 197:511–512CrossRefPubMedGoogle Scholar
  64. Sharma JM (1981) Natural killer cell activity in chickens exposed to Marek's disease virus: inhibition of activity in susceptible chickens and enhancement of activity in resistant and vaccinated chickens. Avian Dis 25(4):882–893CrossRefPubMedGoogle Scholar
  65. Sharma JM, Okazaki W (1981) Natural killer cell activity in chickens: target cell analysis and effect of antithymocyte serum on effector cells. Infect Immun 31(3):1078–1085PubMedPubMedCentralGoogle Scholar
  66. Shaw I, Powell TJ, Marston DA, Baker K, van Hateren A, Riegert P, Wiles MV, Milne S, Beck S, Kaufman J (2007) Different evolutionary histories of the two classical class I genes BF1 and BF2 illustrate drift and selection within the stable MHC haplotypes of chickens. J Immunol 178:5744–5752CrossRefPubMedGoogle Scholar
  67. Smyth JR Jr, McNeil M (1999) Alopecia areata and universalis in the Smyth chicken model for spontaneous autoimmune vitiligo. J Investig Dermatol Symp Proc 4(3):211–215CrossRefPubMedGoogle Scholar
  68. Snyder GA, Brooks AG, Sun PD (1999) Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2. Proc Natl Acad Sci U S A 96(7):3864–3869CrossRefPubMedPubMedCentralGoogle Scholar
  69. Thacker EL, Fulton JE, Hunt HD (1995) In vitro analysis of a primary, major histocompatibility complex (MHC)- restricted, cytotoxic T-lymphocyte response to avian leukosis virus (ALV), using target cells expressing MHC class I cDNA inserted into a recombinant ALV vector. J Virol 69(10):6439–6444PubMedPubMedCentralGoogle Scholar
  70. Tomasec P, Braud VM, Rickards C, Powell MB, McSharry BP, Gadola S, Cerundolo V, Borysiewicz LK, McMichael AJ, Wilkinson GW (2000) Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287(5455):1031CrossRefPubMedGoogle Scholar
  71. Tulman ER, Afonso CL, Lu Z, Zsak L, Rock DL, Kutish GF (2000) The genome of a very virulent Marek’s disease virus. J Virol 74(17):7980–7988CrossRefPubMedPubMedCentralGoogle Scholar
  72. Vales-Gomez M, Browne H, Reyburn HT (2003) Expression of the UL16 glycoprotein of human cytomegalovirus protects the virus-infected cell from attack by natural killer cells. BMC Immunol 4(1):4CrossRefPubMedPubMedCentralGoogle Scholar
  73. Viertlboeck BC, Habermann FA, Schmitt R, Groenen MA, Du Pasquier L, Gobel TW (2005) The chicken leukocyte receptor complex: a highly diverse multigene family encoding at least six structurally distinct receptor types. J Immunol 175(1):385–393CrossRefPubMedGoogle Scholar
  74. Viertlboeck BC, Schmitt R, Gobel TW (2006) The chicken immunoregulatory receptor families SIRP, TREM, and CMRF35/CD300L. Immunogenetics 58(2–3):180–190CrossRefPubMedGoogle Scholar
  75. Walker BA, Hunt LG, Sowa AK, Skjodt K, Gobel TW, Lehner PJ, Kaufman J (2011) The dominantly expressed class I molecule of the chicken MHC is explained by coevolution with the polymorphic peptide transporter (TAP) genes. Proc Natl Acad Sci U S A 108(20):8396–8401CrossRefPubMedPubMedCentralGoogle Scholar
  76. Wallny HJ, Avila D, Hunt LG, Powell TJ, Riegert P, Salomonsen J, Skjodt K, Vainio O, Vilbois F, Wiles MV, Kaufman J (2006) Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens. Proc Natl Acad Sci U S A 103(5):1434–1439CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018
corrected publication July/2018

Authors and Affiliations

  1. 1.United States Department of Agriculture, Agricultural Research Service, U.S. National Poultry Research CenterAthensUSA
  2. 2.Department of Animal and Food ScienceUniversity of DelawareNewarkUSA
  3. 3.Department of PathobiologyAuburn UniversityAuburnUSA
  4. 4.Department of Poultry ScienceAuburn UniversityAuburnUSA

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