Immunogenetics

, Volume 70, Issue 4, pp 209–222 | Cite as

Impact of a CD4 gene haplotype on the immune response in minipigs

  • Fany Blanc
  • Françoise Créchet
  • Nicolas Bruneau
  • Guillaume Piton
  • Jean-Jacques Leplat
  • Fabrice Andréoletti
  • Giorgia Egidy
  • Silvia Vincent-Naulleau
  • Emmanuelle Bourneuf
Original Article

Abstract

The cluster of differentiation 4 (CD4) molecule functions as a co-receptor for MHC class II binding to TCR in T helper cells. A CD4 epitope deficiency was identified in the swine MeLiM (melanoblastoma-bearing Libechov minipig) strain, a model for spontaneous cutaneous melanoma development and regression. Extensive sequencing revealed a high genetic variability of CD4 and the existence of several haplotypes segregating in MeLiM. Forty polymorphisms were identified in the coding sequence, out of which 20 correspond to non-synonymous variants and 10 are located in the 3′UTR of CD4 transcripts. One of the haplotypes segregating in the MeLiM explained the epitope deficiency observed. An association analysis between CD4 genotype and several phenotypes related to tumor regression was performed in 267 animals. An association was evidenced between a MeLiM alternative CD4 haplotype and skin and eye depigmentation, as well as the extent of hair depigmentation. Also, seric IgG concentration was shown to be higher in pigs carrying the alternative haplotype at the homozygous state. In conclusion, the genetic variability of the CD4 gene is associated with immune response-related phenotypes in MeLiM minipigs.

Keywords

CD4 Pig Depigmentation Polymorphism Melanoma Seric IgG levels 

Notes

Acknowledgments

FB was a post-doctoral fellow from Institut National du Cancer. The authors are thankful to D Esquerré and Dr J Estellé who initially performed and analyzed whole genome sequencing of MeLiM (INRA Plateforme Génomique in Toulouse and GABI unit). Finally, the authors wish to acknowledge Dr N Bertho, Dr I Schwartz-Cornil, and Dr A Prévost-Blondel for fruitful discussions and Dr Bertrand Bed’Hom and Dr Claire Rogel-Gaillard for active support.

Compliance with ethical standards

All animal experiments were carried out according to European ethical laws and under approval of the Committee on the Ethics of Animal Experiments.

References

  1. Bach MA, Phan-Dinh-Tuy F, Bach JF et al (1981) Unusual phenotypes of human inducer T cells as measured by OKT4 and related monoclonal antibodies. J Immunol (Baltimore, Md: 1950) 127:980–982Google Scholar
  2. Bendl J, Stourac J, Salanda O et al (2014) PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput Biol 10:e1003440CrossRefPubMedPubMedCentralGoogle Scholar
  3. Boscariol R, Pleasance J, Piedrafita DM et al (2006) Identification of two allelic forms of ovine CD4 exhibiting a Ser183/Pro183 polymorphism in the coding sequence of domain 3. Vet Immunol Immunopathol 113:305–312.  https://doi.org/10.1016/j.vetimm.2006.05.015 CrossRefPubMedGoogle Scholar
  4. Bowman MR, MacFerrin KD, Schreiber SL, Burakoff SJ (1990) Identification and structural analysis of residues in the V1 region of CD4 involved in interaction with human immunodeficiency virus envelope glycoprotein gp120 and class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A 87:9052–9056CrossRefPubMedPubMedCentralGoogle Scholar
  5. Capparelli R, Costabile A, Viscardi M, Iannelli D (2004) Monoallelic expression of mouse Cd4 gene. Mamm Genome 15:579–584.  https://doi.org/10.1007/s00335-004-2351-y CrossRefPubMedGoogle Scholar
  6. Choi RY, Farquhar C, Juno J et al (2010) Infant CD4 C868T polymorphism is associated with increased human immunodeficiency virus (HIV-1) acquisition. Clin Exp Immunol 160:461–465.  https://doi.org/10.1111/j.1365-2249.2010.04096.x CrossRefPubMedPubMedCentralGoogle Scholar
  7. Clark SJ, Jefferies WA, Barclay AN et al (1987) Peptide and nucleotide sequences of rat CD4 (W3/25) antigen: evidence for derivation from a structure with four immunoglobulin-related domains. Proc Natl Acad Sci U S A 84:1649–1653CrossRefPubMedPubMedCentralGoogle Scholar
  8. Clayton LK, Sieh M, Pious DA, Reinherz EL (1989) Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding. Nature 339:548–551.  https://doi.org/10.1038/339548a0 CrossRefPubMedGoogle Scholar
  9. Fleury S, Lamarre D, Meloche S et al (1991) Mutational analysis of the interaction between CD4 and class II MHC: class II antigens contact CD4 on a surface opposite the gp120-binding site. Cell 66:1037–1049CrossRefPubMedGoogle Scholar
  10. Fournier M, Peyrou M, Bourgoin L et al (2010) CD4 dimerization requires two cysteines in the cytoplasmic domain of the molecule and occurs in microdomains distinct from lipid rafts. Mol Immunol 47:2594–2603.  https://doi.org/10.1016/j.molimm.2010.06.010 CrossRefPubMedGoogle Scholar
  11. Gustafsson K, Germana S, Sundt TM et al (1993) Extensive allelic polymorphism in the CDR2-like region of the miniature swine CD4 molecule. J Immunol (Baltimore, Md: 1950) 151:1365–1370Google Scholar
  12. Hruban V, Horak V, Fortyn K et al (2004) Inheritance of malignant melanoma in the MeLiM strain of miniature pigs. Vet Med 49:453–459CrossRefGoogle Scholar
  13. Huang B, Yachou A, Fleury S et al (1997) Analysis of the contact sites on the CD4 molecule with class II MHC molecule: co-ligand versus co-receptor function. J Immunol 158:216–225PubMedGoogle Scholar
  14. Jönsson P, Southcombe JH, Santos AM et al (2016) Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions. Proc Natl Acad Sci 113:5682–5687.  https://doi.org/10.1073/pnas.1513918113 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kristiansen OP, Karlsen a E, Larsen ZM et al (2004) Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity. Scand J Immunol 59:582–591.  https://doi.org/10.1111/j.1365-3083.2004.01444.x CrossRefPubMedGoogle Scholar
  16. Lederman S, DeMartino JA, Daugherty BL et al (1991) A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4. Mol Immunol 28:1171–1181CrossRefPubMedGoogle Scholar
  17. Matsubara T, Nishii N, Takashima S et al (2015) Identification of a CD4 variant in Microminipigs not detectable with available anti-CD4 monoclonal antibodies. Vet Immunol Immunopathol 168:176–183.  https://doi.org/10.1016/j.vetimm.2015.09.008 CrossRefPubMedGoogle Scholar
  18. Matsubara T, Nishii N, Takashima S et al (2016) Identification and characterization of two CD4 alleles in Microminipigs. BMC Vet Res 12:222.  https://doi.org/10.1186/s12917-016-0856-8 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Moebius U, Clayton LK, Abraham S et al (1992) Human immunodeficiency virus gp120 binding C′C″ ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A 89:12008–12012CrossRefPubMedPubMedCentralGoogle Scholar
  20. Morrison WI, Howard CJ, Hinson CJ et al (1994) Identification of three distinct allelic forms of bovine CD4. Immunology 83:589–594PubMedPubMedCentralGoogle Scholar
  21. Oyugi JO, Vouriot FCM, Alimonti J et al (2009) A common CD4 gene variant is associated with an increased risk of HIV-1 infection in Kenyan female commercial sex workers. J Infect Dis 199:1327–1334.  https://doi.org/10.1086/597616 CrossRefPubMedGoogle Scholar
  22. Rambow F, Piton G, Bouet S et al (2008) Gene expression signature for spontaneous cancer regression in melanoma pigs. Neoplasia (New York, NY) 10:714–726, 1 p following 726.  https://doi.org/10.1593/neo.08344 CrossRefGoogle Scholar
  23. Rudd C, Helms S, Barber EK, Schlossman SF (1989) The CD4/CD8:p56lck complex in T lymphocytes: a potential mechanism to regulate T-cell growth. Biochem Cell Biol 67:581–589CrossRefPubMedGoogle Scholar
  24. Shaw AS, Chalupny J, Whitney JA et al (1990) Short related sequences in the cytoplasmic domains of CD4 and CD8 mediate binding to the amino-terminal domain of the p56lck tyrosine protein kinase. Mol Cell Biol 10:1853–1862CrossRefPubMedPubMedCentralGoogle Scholar
  25. Sundt TM, LeGuern C, Germana S et al (1992) Characterization of a polymorphism of CD4 in miniature swine. J Immunol (Baltimore, Md: 1950) 148:3195–3201Google Scholar
  26. Teulings H-E, Limpens J, Jansen SN et al (2015) Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol Off J Am Soc Clin Oncol 33:773–781.  https://doi.org/10.1200/JCO.2014.57.4756 CrossRefGoogle Scholar
  27. Vincent-Naulleau S, Le Chalony C, Leplat JJ et al (2004) Clinical and histopathological characterization of cutaneous melanomas in the melanoblastoma-bearing Libechov minipig model. Pigment Cell Res 17:24–35.  https://doi.org/10.1046/j.1600-0749.2003.00101.x CrossRefPubMedGoogle Scholar
  28. Wang XX, Li Y, Yin Y et al (2011) Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4–HLA-DR1 complex. Proc Natl Acad Sci 108:15960–15965.  https://doi.org/10.1073/pnas.1109438108 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Yang J, Yan R, Roy A et al (2015) The I-TASSER suite: protein structure and function prediction. Nat Methods 12:7–8CrossRefPubMedPubMedCentralGoogle Scholar
  30. Zamani M, Tabatabaiefar MA, Mosayyebi S et al (2009) Possible association of the CD4 gene polymorphism with vitiligo in an Iranian population. Clin Exp Dermatol 35:521–524.  https://doi.org/10.1111/j.1365-2230.2009.03667.x CrossRefPubMedGoogle Scholar
  31. Zhang ZD, Weinstock G, Gerstein M (2008) Rapid evolution by positive Darwinian selection in T-cell antigen CD4 in primates. J Mol Evol 66:446–456.  https://doi.org/10.1007/s00239-008-9097-1 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Fany Blanc
    • 1
    • 2
    • 3
  • Françoise Créchet
    • 1
    • 2
  • Nicolas Bruneau
    • 1
    • 2
  • Guillaume Piton
    • 1
    • 2
  • Jean-Jacques Leplat
    • 1
    • 2
  • Fabrice Andréoletti
    • 1
    • 2
  • Giorgia Egidy
    • 1
    • 2
  • Silvia Vincent-Naulleau
    • 1
    • 2
  • Emmanuelle Bourneuf
    • 1
    • 2
  1. 1.LREG, CEAUniversité Paris-SaclayJouy-en-JosasFrance
  2. 2.GABI, INRA, AgroParisTechUniversité Paris-SaclayJouy-en-JosasFrance
  3. 3.Inserm, U1016, Institut CochinParisFrance

Personalised recommendations