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. 1993 Apr 1;177(4):979–987. doi: 10.1084/jem.177.4.979

Evolutionary conservation of major histocompatibility complex- DR/peptide/T cell interactions in primates

PMCID: PMC2190985  PMID: 8459225

Abstract

Many major histocompatibility complex (MHC) polymorphisms originate from ancient structures that predate speciation. As a consequence, members of the Mhc-DRB1*03 allelic lineage are not only present in humans but in chimpanzees and rhesus macaques as well. This emphasizes that Mhc-DRB1*03 members must have been present in a common ancestor of these primate species that lived about 30 million years ago. Due to the accumulation of genetic variation, however, alleles of the Mhc-DRB1*03 lineage exhibit species-unique sequences. To investigate the biological importance of such conservation and variation, we have studied both the binding and antigen presentation capacity of various trans-species Mhc- DRB1*03 lineage members. Here we show that p3-13 of the 65-kD heat- shock protein (hsp65) of Mycobacterium leprae and M. tuberculosis binds not only to HLA-DR17(3) but also to some chimpanzee and rhesus macaque class II-positive cells. Comparison of the corresponding human, chimpanzee, and rhesus macaque Mhc-DRB1*03 lineage members revealed the presence of uniquely shared amino acid residues, at positions 9-13 and 26-31, of the antigen-binding site that are critical for p3-13 binding. In addition it is shown that several nonhuman primate antigen- presenting cells that bind p3-13 can activate HLA-DR17-restricted T cells. Certain amino acid replacements, however, in Mhc-DRB1*03 lineage members did not influence peptide binding or T cell recognition. Therefore, these studies demonstrate that some polymorphic amino acid residues (motifs) within the antigen-binding site of MHC class II molecules that are crucial for peptide binding and recognition by the T cell receptor have been conserved for over 30 million years.

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Selected References

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  1. Anderson D. C., van Schooten W. C., Janson A., Barry M. E., de Vries R. R. Molecular mapping of interactions between a Mycobacterium leprae-specific T cell epitope, the restricting HLA-DR2 molecule, and two specific T cell receptors. J Immunol. 1990 Apr 1;144(7):2459–2464. [PubMed] [Google Scholar]
  2. Babbitt B. P., Matsueda G., Haber E., Unanue E. R., Allen P. M. Antigenic competition at the level of peptide-Ia binding. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4509–4513. doi: 10.1073/pnas.83.12.4509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Belich M. P., Madrigal J. A., Hildebrand W. H., Zemmour J., Williams R. C., Luz R., Petzl-Erler M. L., Parham P. Unusual HLA-B alleles in two tribes of Brazilian Indians. Nature. 1992 May 28;357(6376):326–329. doi: 10.1038/357326a0. [DOI] [PubMed] [Google Scholar]
  4. Benoist C. O., Mathis D. J., Kanter M. R., Williams V. E., 2nd, McDevitt H. O. Regions of allelic hypervariability in the murine A alpha immune response gene. Cell. 1983 Aug;34(1):169–177. doi: 10.1016/0092-8674(83)90147-2. [DOI] [PubMed] [Google Scholar]
  5. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. doi: 10.1038/329506a0. [DOI] [PubMed] [Google Scholar]
  6. Bontrop R. E., Broos L. A., Pham K., Bakas R. M., Otting N., Jonker M. The chimpanzee major histocompatibility complex class II DR subregion contains an unexpectedly high number of beta-chain genes. Immunogenetics. 1990;32(4):272–280. doi: 10.1007/BF00187098. [DOI] [PubMed] [Google Scholar]
  7. Bontrop R. E., Elferink D. G., Otting N., Jonker M., de Vries R. R. Major histocompatibility complex class II-restricted antigen presentation across a species barrier: conservation of restriction determinants in evolution. J Exp Med. 1990 Jul 1;172(1):53–59. doi: 10.1084/jem.172.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown J. H., Jardetzky T., Saper M. A., Samraoui B., Bjorkman P. J., Wiley D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. doi: 10.1038/332845a0. [DOI] [PubMed] [Google Scholar]
  9. Busch R., Strang G., Howland K., Rothbard J. B. Degenerate binding of immunogenic peptides to HLA-DR proteins on B cell surfaces. Int Immunol. 1990;2(5):443–451. doi: 10.1093/intimm/2.5.443. [DOI] [PubMed] [Google Scholar]
  10. Buus S., Sette A., Grey H. M. The interaction between protein-derived immunogenic peptides and Ia. Immunol Rev. 1987 Aug;98:115–141. doi: 10.1111/j.1600-065x.1987.tb00522.x. [DOI] [PubMed] [Google Scholar]
  11. Erlich H. A., Gyllensten U. B. The evolution of allelic diversity at the primate major histocompatibility complex class II loci. Hum Immunol. 1991 Feb;30(2):110–118. doi: 10.1016/0198-8859(91)90079-o. [DOI] [PubMed] [Google Scholar]
  12. Fan W. M., Kasahara M., Gutknecht J., Klein D., Mayer W. E., Jonker M., Klein J. Shared class II MHC polymorphisms between humans and chimpanzees. Hum Immunol. 1989 Oct;26(2):107–121. doi: 10.1016/0198-8859(89)90096-7. [DOI] [PubMed] [Google Scholar]
  13. GUNDERS A. E. Progressive experimental infection with Mycobacterium leprae in a chimpanzee; a preliminary report. J Trop Med Hyg. 1958 Sep;61(9):228–230. [PubMed] [Google Scholar]
  14. Geluk A., Bloemhoff W., De Vries R. R., Ottenhoff T. H. Binding of a major T cell epitope of mycobacteria to a specific pocket within HLA-DRw17(DR3) molecules. Eur J Immunol. 1992 Jan;22(1):107–113. doi: 10.1002/eji.1830220117. [DOI] [PubMed] [Google Scholar]
  15. Geluk A., Van Meijgaarden K. E., Janson A. A., Drijfhout J. W., Meloen R. H., De Vries R. R., Ottenhoff T. H. Functional analysis of DR17(DR3)-restricted mycobacterial T cell epitopes reveals DR17-binding motif and enables the design of allele-specific competitor peptides. J Immunol. 1992 Nov 1;149(9):2864–2871. [PubMed] [Google Scholar]
  16. Gyllensten U., Sundvall M., Ezcurra I., Erlich H. A. Genetic diversity at class II DRB loci of the primate MHC. J Immunol. 1991 Jun 15;146(12):4368–4376. [PubMed] [Google Scholar]
  17. Hill A. V., Allsopp C. E., Kwiatkowski D., Anstey N. M., Twumasi P., Rowe P. A., Bennett S., Brewster D., McMichael A. J., Greenwood B. M. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991 Aug 15;352(6336):595–600. doi: 10.1038/352595a0. [DOI] [PubMed] [Google Scholar]
  18. Hughes A. L., Nei M. Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. Proc Natl Acad Sci U S A. 1989 Feb;86(3):958–962. doi: 10.1073/pnas.86.3.958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Klein J., Bontrop R. E., Dawkins R. L., Erlich H. A., Gyllensten U. B., Heise E. R., Jones P. P., Parham P., Wakeland E. K., Watkins D. I. Nomenclature for the major histocompatibility complexes of different species: a proposal. Immunogenetics. 1990;31(4):217–219. doi: 10.1007/BF00204890. [DOI] [PubMed] [Google Scholar]
  20. Klein J. Of HLA, tryps, and selection: an essay on coevolution of MHC and parasites. Hum Immunol. 1991 Apr;30(4):247–258. doi: 10.1016/0198-8859(91)90003-r. [DOI] [PubMed] [Google Scholar]
  21. Klein J. Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol. 1987 Jul;19(3):155–162. doi: 10.1016/0198-8859(87)90066-8. [DOI] [PubMed] [Google Scholar]
  22. Lamb J. R., Bal V., Mendez-Samperio P., Mehlert A., So A., Rothbard J., Jindal S., Young R. A., Young D. B. Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1(2):191–196. doi: 10.1093/intimm/1.2.191. [DOI] [PubMed] [Google Scholar]
  23. Lawlor D. A., Ward F. E., Ennis P. D., Jackson A. P., Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature. 1988 Sep 15;335(6187):268–271. doi: 10.1038/335268a0. [DOI] [PubMed] [Google Scholar]
  24. Leininger J. R., Donham K. J., Rubino M. J. Leprosy in a chimpanzee. Morphology of the skin lesions and characterization of the organism. Vet Pathol. 1978 May;15(3):339–346. doi: 10.1177/030098587801500308. [DOI] [PubMed] [Google Scholar]
  25. Levinson G., Hughes A. L., Letvin N. L. Sequence and diversity of rhesus monkey T-cell receptor beta chain genes. Immunogenetics. 1992;35(2):75–88. doi: 10.1007/BF00189516. [DOI] [PubMed] [Google Scholar]
  26. Marsh S. G., Bodmer J. G. HLA class II nucleotide sequences, 1991. Hum Immunol. 1991 Jul;31(3):207–227. doi: 10.1016/0198-8859(91)90027-7. [DOI] [PubMed] [Google Scholar]
  27. Mayer W. E., Jonker M., Klein D., Ivanyi P., van Seventer G., Klein J. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J. 1988 Sep;7(9):2765–2774. doi: 10.1002/j.1460-2075.1988.tb03131.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miyamoto M. M., Koop B. F., Slightom J. L., Goodman M., Tennant M. R. Molecular systematics of higher primates: genealogical relations and classification. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7627–7631. doi: 10.1073/pnas.85.20.7627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mulder J. B. Tuberculosis in non-human primates. Vet Med Small Anim Clin. 1976 Sep;71(9):1286–1287. [PubMed] [Google Scholar]
  30. Ottenhoff T. H., Ab B. K., Van Embden J. D., Thole J. E., Kiessling R. The recombinant 65-kD heat shock protein of Mycobacterium bovis Bacillus Calmette-Guerin/M. tuberculosis is a target molecule for CD4+ cytotoxic T lymphocytes that lyse human monocytes. J Exp Med. 1988 Nov 1;168(5):1947–1952. doi: 10.1084/jem.168.5.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ottenhoff T. H., Haanen J. B., Geluk A., Mutis T., Ab B. K., Thole J. E., van Schooten W. C., van den Elsen P. J., de Vries R. R. Regulation of mycobacterial heat-shock protein-reactive T cells by HLA class II molecules: lessons from leprosy. Immunol Rev. 1991 Jun;121:171–191. doi: 10.1111/j.1600-065x.1991.tb00828.x. [DOI] [PubMed] [Google Scholar]
  32. Otting N., Kenter M., van Weeren P., Jonker M., Bontrop R. E. Mhc-DQB repertoire variation in hominoid and Old World primate species. J Immunol. 1992 Jul 15;149(2):461–470. [PubMed] [Google Scholar]
  33. Rock K. L., Benacerraf B. Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. Evidence of specific competition for accessory cell antigen presentation. J Exp Med. 1983 May 1;157(5):1618–1634. doi: 10.1084/jem.157.5.1618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rothbard J. B., Busch R., Howland K., Bal V., Fenton C., Taylor W. R., Lamb J. R. Structural analysis of a peptide--HLA class II complex: identification of critical interactions for its formation and recognition by T cell receptor. Int Immunol. 1989;1(5):479–486. doi: 10.1093/intimm/1.5.479. [DOI] [PubMed] [Google Scholar]
  35. Schwartz R. H. T-lymphocyte recognition of antigen in association with gene products of the major histocompatibility complex. Annu Rev Immunol. 1985;3:237–261. doi: 10.1146/annurev.iy.03.040185.001321. [DOI] [PubMed] [Google Scholar]
  36. Serjeantson S. W. The reasons for MHC polymorphism in man. Transplant Proc. 1989 Feb;21(1 Pt 1):598–601. [PubMed] [Google Scholar]
  37. Sigurdardóttir S., Borsch C., Gustafsson K., Andersson L. Exon encoding the antigen-binding site of MHC class II beta-chains is divided into two subregions with different evolutionary histories. J Immunol. 1992 Feb 1;148(3):968–973. [PubMed] [Google Scholar]
  38. Slierendregt B. L., Otting N., Jonker M., Bontrop R. E. RFLP analysis of the rhesus monkey MHC class II DR subregion. Hum Immunol. 1991 Jan;30(1):11–17. doi: 10.1016/0198-8859(91)90064-g. [DOI] [PubMed] [Google Scholar]
  39. Slierendregt B. L., van Noort J. T., Bakas R. M., Otting N., Jonker M., Bontrop R. E. Evolutionary stability of transspecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys. Hum Immunol. 1992 Sep;35(1):29–39. doi: 10.1016/0198-8859(92)90092-2. [DOI] [PubMed] [Google Scholar]
  40. Thole J. E., Keulen W. J., De Bruyn J., Kolk A. H., Groothuis D. G., Berwald L. G., Tiesjema R. H., van Embden J. D. Characterization, sequence determination, and immunogenicity of a 64-kilodalton protein of Mycobacterium bovis BCG expressed in escherichia coli K-12. Infect Immun. 1987 Jun;55(6):1466–1475. doi: 10.1128/iai.55.6.1466-1475.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Van Schooten W. C., Elferink D. G., Van Embden J., Anderson D. C., De Vries R. R. DR3-restricted T cells from different HLA-DR3-positive individuals recognize the same peptide (amino acids 2-12) of the mycobacterial 65-kDa heat-shock protein. Eur J Immunol. 1989 Nov;19(11):2075–2079. doi: 10.1002/eji.1830191116. [DOI] [PubMed] [Google Scholar]
  42. Watkins D. I., McAdam S. N., Liu X., Strang C. R., Milford E. L., Levine C. G., Garber T. L., Dogon A. L., Lord C. I., Ghim S. H. New recombinant HLA-B alleles in a tribe of South American Amerindians indicate rapid evolution of MHC class I loci. Nature. 1992 May 28;357(6376):329–333. doi: 10.1038/357329a0. [DOI] [PubMed] [Google Scholar]
  43. Werdelin O. Chemically related antigens compete for presentation by accessory cells to T cells. J Immunol. 1982 Nov;129(5):1883–1891. [PubMed] [Google Scholar]
  44. Wolf R. H., Gormus B. J., Martin L. N., Baskin G. B., Walsh G. P., Meyers W. M., Binford C. H. Experimental leprosy in three species of monkeys. Science. 1985 Feb 1;227(4686):529–531. doi: 10.1126/science.3917577. [DOI] [PubMed] [Google Scholar]
  45. Young D., Lathigra R., Hendrix R., Sweetser D., Young R. A. Stress proteins are immune targets in leprosy and tuberculosis. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4267–4270. doi: 10.1073/pnas.85.12.4267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]

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