Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Sep 1;182(3):733–741. doi: 10.1084/jem.182.3.733

HLA-DR polymorphism affects the interaction with CD4

PMCID: PMC2192178  PMID: 7650480

Abstract

Major histocompatibility complex (MHC) class II molecules are highly polymorphic and bind peptides for presentation to CD4+ T cells. Functional and adhesion assays have shown that CD4 interacts with MHC class II molecules, leading to enhanced responses of CD4+ T cells after the activation of the CD4-associated tyrosine kinase p56lck. We have addressed the possible contribution of allelic polymorphism in the interaction between CD4 and MHC class II molecules. Using mouse DAP-3- transfected cells expressing different isotypes and allelic forms of the HLA-DR molecule, we have shown in a functional assay that a hierarchy exists in the ability of class II molecules to interact with CD4. Also, the study of DR4 subtypes minimized the potential contribution of polymorphic residues of the peptide-binding groove in the interaction with CD4. Chimeras between the DR4 or DR1 molecules, which interact efficiently with CD4, and DRw53, which interacts poorly, allowed the mapping of polymorphic residues between positions beta 180 and 189 that can exert a dramatic influence on the interaction with CD4.

Full Text

The Full Text of this article is available as a PDF (3.0 MB).

Selected References

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

  1. Aldrich C. J., Hammer R. E., Jones-Youngblood S., Koszinowski U., Hood L., Stroynowski I., Forman J. Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the alpha 3 domain of MHC I molecules. Nature. 1991 Aug 22;352(6337):718–721. doi: 10.1038/352718a0. [DOI] [PubMed] [Google Scholar]
  2. Brown J. H., Jardetzky T. S., Gorga J. C., Stern L. J., Urban R. G., Strominger J. L., Wiley D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. doi: 10.1038/364033a0. [DOI] [PubMed] [Google Scholar]
  3. Cammarota G., Scheirle A., Takacs B., Doran D. M., Knorr R., Bannwarth W., Guardiola J., Sinigaglia F. Identification of a CD4 binding site on the beta 2 domain of HLA-DR molecules. Nature. 1992 Apr 30;356(6372):799–801. doi: 10.1038/356799a0. [DOI] [PubMed] [Google Scholar]
  4. Didier D. K., Schiffenbauer J., Shuman S., Abruzzini L. F., Gorski J., Watling D. L., Tieber V. L., Schwartz B. D. Characterization of two distinct DR beta chain alleles at the beta III locus of the DR5 haplotype: beta III alleles are highly conserved. J Immunol. 1986 Oct 15;137(8):2627–2631. [PubMed] [Google Scholar]
  5. Doyle C., Strominger J. L. Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature. 1987 Nov 19;330(6145):256–259. doi: 10.1038/330256a0. [DOI] [PubMed] [Google Scholar]
  6. Fleury S., Lamarre D., Meloche S., Ryu S. E., Cantin C., Hendrickson W. A., Sekaly R. P. 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. 1991 Sep 6;66(5):1037–1049. doi: 10.1016/0092-8674(91)90447-7. [DOI] [PubMed] [Google Scholar]
  7. Gay D., Buus S., Pasternak J., Kappler J., Marrack P. The T-cell accessory molecule CD4 recognizes a monomorphic determinant on isolated Ia. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5629–5633. doi: 10.1073/pnas.85.15.5629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gay D., Maddon P., Sekaly R., Talle M. A., Godfrey M., Long E., Goldstein G., Chess L., Axel R., Kappler J. Functional interaction between human T-cell protein CD4 and the major histocompatibility complex HLA-DR antigen. Nature. 1987 Aug 13;328(6131):626–629. doi: 10.1038/328626a0. [DOI] [PubMed] [Google Scholar]
  9. Glaichenhaus N., Shastri N., Littman D. R., Turner J. M. Requirement for association of p56lck with CD4 in antigen-specific signal transduction in T cells. Cell. 1991 Feb 8;64(3):511–520. doi: 10.1016/0092-8674(91)90235-q. [DOI] [PubMed] [Google Scholar]
  10. Gorski J., Irle C., Mickelson E. M., Sheehy M. J., Termijtelen A., Ucla C., Mach B. Correlation of structure with T cell responses of the three members of the HLA-DRw52 allelic series. J Exp Med. 1989 Sep 1;170(3):1027–1032. doi: 10.1084/jem.170.3.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  12. Greenstein J. L., Kappler J., Marrack P., Burakoff S. J. The role of L3T4 in recognition of Ia by a cytotoxic, H-2Dd-specific T cell hybridoma. J Exp Med. 1984 Apr 1;159(4):1213–1224. doi: 10.1084/jem.159.4.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gregersen P. K., Moriuchi T., Karr R. W., Obata F., Moriuchi J., Maccari J., Goldberg D., Winchester R. J., Silver J. Polymorphism of HLA-DR beta chains in DR4, -7, and -9 haplotypes: implications for the mechanisms of allelic variation. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9149–9153. doi: 10.1073/pnas.83.23.9149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gregersen P. K., Shen M., Song Q. L., Merryman P., Degar S., Seki T., Maccari J., Goldberg D., Murphy H., Schwenzer J. Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2642–2646. doi: 10.1073/pnas.83.8.2642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Houlgatte R., Scarmato P., el Marhomy S., Martin M., Ostankovitch M., Lafosse S., Vervisch A., Auffray C., Platier-Tonneau D. HLA class II antigens and the HIV envelope glycoprotein gp120 bind to the same face of CD4. J Immunol. 1994 May 1;152(9):4475–4488. [PubMed] [Google Scholar]
  16. Jaraquemada D., Martin R., Rosen-Bronson S., Flerlage M., McFarland H. F., Long E. O. HLA-DR2a is the dominant restriction molecule for the cytotoxic T cell response to myelin basic protein in DR2Dw2 individuals. J Immunol. 1990 Nov 1;145(9):2880–2885. [PubMed] [Google Scholar]
  17. Kozlowski S., Takeshita T., Boehncke W. H., Takahashi H., Boyd L. F., Germain R. N., Berzofsky J. A., Margulies D. H. Excess beta 2 microglobulin promoting functional peptide association with purified soluble class I MHC molecules. Nature. 1991 Jan 3;349(6304):74–77. doi: 10.1038/349074a0. [DOI] [PubMed] [Google Scholar]
  18. König R., Huang L. Y., Germain R. N. MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8. Nature. 1992 Apr 30;356(6372):796–798. doi: 10.1038/356796a0. [DOI] [PubMed] [Google Scholar]
  19. Lamarre D., Ashkenazi A., Fleury S., Smith D. H., Sekaly R. P., Capon D. J. The MHC-binding and gp120-binding functions of CD4 are separable. Science. 1989 Aug 18;245(4919):743–746. doi: 10.1126/science.2549633. [DOI] [PubMed] [Google Scholar]
  20. Lamarre D., Capon D. J., Karp D. R., Gregory T., Long E. O., Sékaly R. P. Class II MHC molecules and the HIV gp 120 envelope protein interact with functionally distinct regions of the CD4 molecule. EMBO J. 1989 Nov;8(11):3271–3277. doi: 10.1002/j.1460-2075.1989.tb08487.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lee B. S., Rust N. A., McMichael A. J., McDevitt H. O. HLA-DR2 subtypes form an additional supertypic family of DR beta alleles. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4591–4595. doi: 10.1073/pnas.84.13.4591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Long E. O., Rosen-Bronson S., Karp D. R., Malnati M., Sekaly R. P., Jaraquemada D. Efficient cDNA expression vectors for stable and transient expression of HLA-DR in transfected fibroblast and lymphoid cells. Hum Immunol. 1991 Aug;31(4):229–235. doi: 10.1016/0198-8859(91)90092-n. [DOI] [PubMed] [Google Scholar]
  23. Marrack P., Kappler J. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. Adv Immunol. 1986;38:1–30. doi: 10.1016/s0065-2776(08)60005-x. [DOI] [PubMed] [Google Scholar]
  24. Moebius U., Pallai P., Harrison S. C., Reinherz E. L. Delineation of an extended surface contact area on human CD4 involved in class II major histocompatibility complex binding. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8259–8263. doi: 10.1073/pnas.90.17.8259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Norment A. M., Salter R. D., Parham P., Engelhard V. H., Littman D. R. Cell-cell adhesion mediated by CD8 and MHC class I molecules. Nature. 1988 Nov 3;336(6194):79–81. doi: 10.1038/336079a0. [DOI] [PubMed] [Google Scholar]
  26. Ottenhoff T. H., Elferink D. G., Hermans J., de Vries R. R. HLA class II restriction repertoire of antigen-specific T cells. I. The main restriction determinants for antigen presentation are associated with HLA-D/DR and not with DP and DQ. Hum Immunol. 1985 Jun;13(2):105–116. doi: 10.1016/0198-8859(85)90017-5. [DOI] [PubMed] [Google Scholar]
  27. Potter T. A., Rajan T. V., Dick R. F., 2nd, Bluestone J. A. Substitution at residue 227 of H-2 class I molecules abrogates recognition by CD8-dependent, but not CD8-independent, cytotoxic T lymphocytes. Nature. 1989 Jan 5;337(6202):73–75. doi: 10.1038/337073a0. [DOI] [PubMed] [Google Scholar]
  28. Rosenstein Y., Burakoff S. J., Herrmann S. H. HIV-gp120 can block CD4-class II MHC-mediated adhesion. J Immunol. 1990 Jan 15;144(2):526–531. [PubMed] [Google Scholar]
  29. Salter R. D., Benjamin R. J., Wesley P. K., Buxton S. E., Garrett T. P., Clayberger C., Krensky A. M., Norment A. M., Littman D. R., Parham P. A binding site for the T-cell co-receptor CD8 on the alpha 3 domain of HLA-A2. Nature. 1990 May 3;345(6270):41–46. doi: 10.1038/345041a0. [DOI] [PubMed] [Google Scholar]
  30. Sekaly R. P., Tonnelle C., Strubin M., Mach B., Long E. O. Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain. J Exp Med. 1986 Nov 1;164(5):1490–1504. doi: 10.1084/jem.164.5.1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Swain S. L., Dialynas D. P., Fitch F. W., English M. Monoclonal antibody to L3T4 blocks the function of T cells specific for class 2 major histocompatibility complex antigens. J Immunol. 1984 Mar;132(3):1118–1123. [PubMed] [Google Scholar]
  32. Swain S. L. T cell subsets and the recognition of MHC class. Immunol Rev. 1983;74:129–142. doi: 10.1111/j.1600-065x.1983.tb01087.x. [DOI] [PubMed] [Google Scholar]
  33. Takahashi H., Cohen J., Hosmalin A., Cease K. B., Houghten R., Cornette J. L., DeLisi C., Moss B., Germain R. N., Berzofsky J. A. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. doi: 10.1073/pnas.85.9.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tonnelle C., DeMars R., Long E. O. DO beta: a new beta chain gene in HLA-D with a distinct regulation of expression. EMBO J. 1985 Nov;4(11):2839–2847. doi: 10.1002/j.1460-2075.1985.tb04012.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Trowsdale J., Ragoussis J., Campbell R. D. Map of the human MHC. Immunol Today. 1991 Dec;12(12):443–446. doi: 10.1016/0167-5699(91)90017-n. [DOI] [PubMed] [Google Scholar]
  36. Wilkinson D., de Vries R. R., Madrigal J. A., Lock C. B., Morgenstern J. P., Trowsdale J., Altmann D. M. Analysis of HLA-DR glycoproteins by DNA-mediated gene transfer. Definition of DR2 beta gene products and antigen presentation to T cell clones from leprosy patients. J Exp Med. 1988 Apr 1;167(4):1442–1458. doi: 10.1084/jem.167.4.1442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Young J. A., Wilkinson D., Bodmer W. F., Trowsdale J. Sequence and evolution of HLA-DR7- and -DRw53-associated beta-chain genes. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4929–4933. doi: 10.1073/pnas.84.14.4929. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES