Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Jan 1;171(1):85–95. doi: 10.1084/jem.171.1.85

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition

PMCID: PMC2187655  PMID: 2104922

Abstract

18 transfected cell lines were generated that expressed distinct DQ molecules related to the serologically defined HLA-DQw3 specificity. These transfectants were constructed using site-directed mutagenesis to introduce nucleotide substitutions into DQ3.2 beta cDNA, followed by retrovirus-mediated gene expression of the mutagenized genes in human B cell lines with different endogenous DQ alpha chains. The capacity of particular class II dimers to stimulate alloreactive T cell clones was investigated. T cell activation was found to be dependent on both DQ alpha and DQ beta chains. In some cases, single amino acid substitutions at codons 13, 26, 45, or 57 of the DQ beta chain were sufficient to dramatically alter T cell reactivity; T cell recognition of these substitutions, however, was strongly influenced by the alpha chain polymorphisms present in the stimulatory class II dimer. Both gain and loss of major serologic and cellular specificities associated with specific DQw3+ alleles were observed with a limited array of site- directed substitutions.

Full Text

The Full Text of this article is available as a PDF (738.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amar A., Radka S. F., Holbeck S. L., Kim S. J., Nepom B. S., Nelson K., Nepom G. T. Characterization of specific HLA-DQ alpha allospecificities by genomic, biochemical, and serologic analysis. J Immunol. 1987 Jun 1;138(11):3986–3990. [PubMed] [Google Scholar]
  2. Babbitt B. P., Allen P. M., Matsueda G., Haber E., Unanue E. R. Binding of immunogenic peptides to Ia histocompatibility molecules. 1985 Sep 26-Oct 2Nature. 317(6035):359–361. doi: 10.1038/317359a0. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Buerstedde J. M., Nilson A. E., Chase C. G., Bell M. P., Beck B. N., Pease L. R., McKean D. J. A beta polymorphic residues responsible for class II molecule recognition by alloreactive T cells. J Exp Med. 1989 May 1;169(5):1645–1654. doi: 10.1084/jem.169.5.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buus S., Sette A., Colon S. M., Miles C., Grey H. M. The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science. 1987 Mar 13;235(4794):1353–1358. doi: 10.1126/science.2435001. [DOI] [PubMed] [Google Scholar]
  6. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  7. Fathman C. G., Kimoto M., Melvold R., David C. S. Reconstitution of Ir genes, Ia antigens, and mixed lymphocyte reaction determinants by gene complementation. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1853–1857. doi: 10.1073/pnas.78.3.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Germain R. N., Bentley D. M., Quill H. Influence of allelic polymorphism on the assembly and surface expression of class II MHC (Ia) molecules. Cell. 1985 Nov;43(1):233–242. doi: 10.1016/0092-8674(85)90028-5. [DOI] [PubMed] [Google Scholar]
  9. Giles R. C., Nunez G., Hurley C. K., Nunez-Roldan A., Winchester R., Stastny P., Capra J. D. Structural analysis of a human I-A homologue using a monoclonal antibody that recognizes an MB3-like specificity. J Exp Med. 1983 May 1;157(5):1461–1470. doi: 10.1084/jem.157.5.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gonwa T. A. Hybrid Ia antigens in man. Detection with cytotoxic T cell clones. Transplantation. 1986 Oct;42(4):423–429. doi: 10.1097/00007890-198610000-00019. [DOI] [PubMed] [Google Scholar]
  11. Hiraiwa A., Seyfried C. E., Nepom G. T., Milner E. C. Sequence analysis of HLA class II domains: characterization of the DQw3 family of DQB genes. Immunogenetics. 1989;29(3):186–190. doi: 10.1007/BF00373644. [DOI] [PubMed] [Google Scholar]
  12. Holbeck S. L., Nepom G. T. Molecular analysis of DQ beta 3.1 genes. Hum Immunol. 1988 Mar;21(3):183–192. doi: 10.1016/0198-8859(88)90070-5. [DOI] [PubMed] [Google Scholar]
  13. Horn G. T., Bugawan T. L., Long C. M., Erlich H. A. Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6012–6016. doi: 10.1073/pnas.85.16.6012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jelachich M. L., Cowan E. P., Turner R. V., Coligan J. E., Biddison W. E. Analysis of the molecular basis of HLA-A3 recognition by cytotoxic T cells using defined mutants of the HLA-A3 molecule. J Immunol. 1988 Aug 15;141(4):1108–1113. [PubMed] [Google Scholar]
  15. Kim S. J., Holbeck S. L., Nisperos B., Hansen J. A., Maeda H., Nepom G. T. Identification of a polymorphic variant associated with HLA-DQw3 and characterized by specific restriction sites within the DQ beta-chain gene. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8139–8143. doi: 10.1073/pnas.82.23.8139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kwok W. W., Lotshaw C., Milner E. C., Knitter-Jack N., Nepom G. T. Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellitus susceptibility gene. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1027–1030. doi: 10.1073/pnas.86.3.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kwok W. W., Schwarz D., Nepom B. S., Hock R. A., Thurtle P. S., Nepom G. T. HLA-DQ molecules form alpha-beta heterodimers of mixed allotype. J Immunol. 1988 Nov 1;141(9):3123–3127. [PubMed] [Google Scholar]
  18. Lee D. R., Hansen T. H., Cullen S. E. Detection of an altered I-A beta polypeptide in the murine Ir mutant, B6.C-h-2bm12. J Immunol. 1982 Jul;129(1):245–251. [PubMed] [Google Scholar]
  19. Maeda H., Hirata R., Kambayashi H., Koning F., Schreuder G. M. Multiple epitopes on a single DQ molecule from the DQw3-carrying haplotypes. Tissue Antigens. 1986 Sep;28(3):136–145. doi: 10.1111/j.1399-0039.1986.tb00473.x. [DOI] [PubMed] [Google Scholar]
  20. McIntyre K. R., Seidman J. G. Nucleotide sequence of mutant I-A beta bm12 gene is evidence for genetic exchange between mouse immune response genes. Nature. 1984 Apr 5;308(5959):551–553. doi: 10.1038/308551a0. [DOI] [PubMed] [Google Scholar]
  21. Mengle-Gaw L., Conner S., McDevitt H. O., Fathman C. G. Gene conversion between murine class II major histocompatibility complex loci. Functional and molecular evidence from the bm 12 mutant. J Exp Med. 1984 Oct 1;160(4):1184–1194. doi: 10.1084/jem.160.4.1184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mickelson E. M., Beatty P. G., Storb R., Hansen J. A. Immune responses in an untransfused patient with aplastic anemia: analysis of cytolytic and proliferative T cell clones. Hum Immunol. 1984 Jul;10(3):189–201. doi: 10.1016/0198-8859(84)90039-9. [DOI] [PubMed] [Google Scholar]
  23. Mickelson E. M., Masewicz S. A., Cotner T., Hansen J. A. Variants of HLA-DRw52 defined by T lymphocyte clones. Hum Immunol. 1988 Aug;22(4):263–274. doi: 10.1016/0198-8859(88)90005-5. [DOI] [PubMed] [Google Scholar]
  24. Monos D. S., Spielman R. S., Gogolin K. J., Radka S. F., Baker L., Zmijewski C. M., Kamoun M. HLA-DQw3.2 allele of the DR4 haplotype is associated with insulin-dependent diabetes; correlation between DQ beta restriction fragments and DQ beta chain variation. Immunogenetics. 1987;26(4-5):299–303. doi: 10.1007/BF00346526. [DOI] [PubMed] [Google Scholar]
  25. Morel P. A., Dorman J. S., Todd J. A., McDevitt H. O., Trucco M. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8111–8115. doi: 10.1073/pnas.85.21.8111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nepom B. S., Palmer J., Kim S. J., Hansen J. A., Holbeck S. L., Nepom G. T. Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. J Exp Med. 1986 Jul 1;164(1):345–350. doi: 10.1084/jem.164.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nepom G. T. Immunogenetics of HLA-associated diseases. Concepts Immunopathol. 1988;5:80–105. [PubMed] [Google Scholar]
  28. Nepom G. T., Nepom B. S., Antonelli P., Mickelson E., Silver J., Goyert S. M., Hansen J. A. The HLA-DR4 family of haplotypes consists of series of distinct DR and DS molecules. J Exp Med. 1984 Feb 1;159(2):394–404. doi: 10.1084/jem.159.2.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nepom G. T. Structural variation among major histocompatibility complex class-II genes which predispose to autoimmunity. Immunol Res. 1989;8(1):16–38. doi: 10.1007/BF02918553. [DOI] [PubMed] [Google Scholar]
  30. Robinson D. M., Holbeck S., Palmer J., Nepom G. T. HLA DQ beta 3.2 identifies subtypes of DR4+ haplotypes permissive for IDDM. Genet Epidemiol. 1989;6(1):149–154. doi: 10.1002/gepi.1370060128. [DOI] [PubMed] [Google Scholar]
  31. Ronchese F., Brown M. A., Germain R. N. Structure-function analysis of the Abm12 beta mutation using site-directed mutagenesis and DNA-mediated gene transfer. J Immunol. 1987 Jul 15;139(2):629–638. [PubMed] [Google Scholar]
  32. Sant A. J., Braunstein N. S., Germain R. N. Predominant role of amino-terminal sequences in dictating efficiency of class II major histocompatibility complex alpha beta dimer expression. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8065–8069. doi: 10.1073/pnas.84.22.8065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schreuder G. M., Tilanus M. G., Bontrop R. E., Bruining G. J., Giphart M. J., van Rood J. J., de Vries R. R. HLA-DO polymorphism associated with resistance to type I diabetes detected with monoclonal antibodies, isoelectric point differences, and restriction fragment length polymorphism. J Exp Med. 1986 Sep 1;164(3):938–943. doi: 10.1084/jem.164.3.938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Todd J. A., Bell J. I., McDevitt H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES