Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Nov 1;182(5):1315–1325. doi: 10.1084/jem.182.5.1315

Human CD8 transgene regulation of HLA recognition by murine T cells

PMCID: PMC2192222  PMID: 7595202

Abstract

A series of human CD8 transgenic (hCD8 Tg) mice with differential expression in the thymus and periphery were produced to investigate CD8 coreceptor regulation of repertoire selection and T cell responses. Expression of hCD8 markedly enhanced responses to both HLA class I molecules and hybrid A2/Kb molecules providing functional evidence for a second interaction site, outside of the alpha 3 domain, which is essential for optimal coreceptor function. Peripheral T cell expression of hCD8 was sufficient to augment responsiveness to HLA class I, as hCD8 Tg mice which lacked thymic expression responded as well as mice expressing hCD8 in the thymus and periphery. Both murine CD8+ and CD4+ T cells expressing hCD8 transgenes exhibited markedly enhanced responses to foreign HLA class I, revealing the ability of T cell receptor repertoires selected on either murine class I or class II to recognize human class I major histocompatibility complex (MHC). In contrast to recognition of foreign class I, thymic expression of hCD8 transgenes was absolutely required to enhance recognition of antigenic peptide restricted by self-HLA class I. Thus, our studies revealed disparate requirements for CD8 coreceptor expression in the thymus for selection of a T cell repertoire responsive to foreign MHC and to antigenic peptides bound to self-MHC, providing a novel demonstration of positive selection that is dependent on human CD8.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Abraham N., Miceli M. C., Parnes J. R., Veillette A. Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck. Nature. 1991 Mar 7;350(6313):62–66. doi: 10.1038/350062a0. [DOI] [PubMed] [Google Scholar]
  2. Chamberlain J. W., Nolan J. A., Conrad P. J., Vasavada H. A., Vasavada H. H., Ploegh H. L., Ganguly S., Janeway C. A., Jr, Weissman S. M. Tissue-specific and cell surface expression of human major histocompatibility complex class I heavy (HLA-B7) and light (beta 2-microglobulin) chain genes in transgenic mice. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7690–7694. doi: 10.1073/pnas.85.20.7690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Crooks M. E., Littman D. R. Disruption of T lymphocyte positive and negative selection in mice lacking the CD8 beta chain. Immunity. 1994 Jul;1(4):277–285. doi: 10.1016/1074-7613(94)90079-5. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. DiSanto J. P., Terry L. A., Flomenberg N. Generation of anti-human CD8 beta-specific antibodies using transfectants expressing mixed-species CD8 heterodimers. J Immunol Methods. 1991 Jul 26;141(1):123–131. doi: 10.1016/0022-1759(91)90218-5. [DOI] [PubMed] [Google Scholar]
  6. Emmrich F., Strittmatter U., Eichmann K. Synergism in the activation of human CD8 T cells by cross-linking the T-cell receptor complex with the CD8 differentiation antigen. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8298–8302. doi: 10.1073/pnas.83.21.8298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fung-Leung W. P., Kündig T. M., Ngo K., Panakos J., De Sousa-Hitzler J., Wang E., Ohashi P. S., Mak T. W., Lau C. Y. Reduced thymic maturation but normal effector function of CD8+ T cells in CD8 beta gene-targeted mice. J Exp Med. 1994 Sep 1;180(3):959–967. doi: 10.1084/jem.180.3.959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fung-Leung W. P., Louie M. C., Limmer A., Ohashi P. S., Ngo K., Chen L., Kawai K., Lacy E., Loh D. Y., Mak T. W. The lack of CD8 alpha cytoplasmic domain resulted in a dramatic decrease in efficiency in thymic maturation but only a moderate reduction in cytotoxic function of CD8+ T lymphocytes. Eur J Immunol. 1993 Nov;23(11):2834–2840. doi: 10.1002/eji.1830231117. [DOI] [PubMed] [Google Scholar]
  9. Fung-Leung W. P., Schilham M. W., Rahemtulla A., Kündig T. M., Vollenweider M., Potter J., van Ewijk W., Mak T. W. CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell. 1991 May 3;65(3):443–449. doi: 10.1016/0092-8674(91)90462-8. [DOI] [PubMed] [Google Scholar]
  10. Garvin A. M., Abraham K. M., Forbush K. A., Farr A. G., Davison B. L., Perlmutter R. M. Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen. Int Immunol. 1990;2(2):173–180. doi: 10.1093/intimm/2.2.173. [DOI] [PubMed] [Google Scholar]
  11. Giblin P. A., Leahy D. J., Mennone J., Kavathas P. B. The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompatibility complex class I molecules: support for a bivalent model. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1716–1720. doi: 10.1073/pnas.91.5.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Holländer G. A., Luskey B. D., Williams D. A., Burakoff S. J. Functional expression of human CD8 in fully reconstituted mice after retroviral-mediated gene transfer of hemopoietic stem cells. J Immunol. 1992 Jul 15;149(2):438–444. [PubMed] [Google Scholar]
  13. Hurley T. R., Luo K., Sefton B. M. Activators of protein kinase C induce dissociation of CD4, but not CD8, from p56lck. Science. 1989 Jul 28;245(4916):407–409. doi: 10.1126/science.2787934. [DOI] [PubMed] [Google Scholar]
  14. Irwin M. J., Heath W. R., Sherman L. A. Species-restricted interactions between CD8 and the alpha 3 domain of class I influence the magnitude of the xenogeneic response. J Exp Med. 1989 Oct 1;170(4):1091–1101. doi: 10.1084/jem.170.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Itano A., Cado D., Chan F. K., Robey E. A role for the cytoplasmic tail of the beta chain of CD8 in thymic selection. Immunity. 1994 Jul;1(4):287–290. doi: 10.1016/1074-7613(94)90080-9. [DOI] [PubMed] [Google Scholar]
  16. Janeway C. A., Jr T-cell development. Accessories or coreceptors? Nature. 1988 Sep 15;335(6187):208–210. doi: 10.1038/335208a0. [DOI] [PubMed] [Google Scholar]
  17. Kalinke U., Arnold B., Hämmerling G. J. Strong xenogeneic HLA response in transgenic mice after introducing an alpha 3 domain into HLA B27. Nature. 1990 Dec 13;348(6302):642–644. doi: 10.1038/348642a0. [DOI] [PubMed] [Google Scholar]
  18. Kaye J., Hsu M. L., Sauron M. E., Jameson S. C., Gascoigne N. R., Hedrick S. M. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature. 1989 Oct 26;341(6244):746–749. doi: 10.1038/341746a0. [DOI] [PubMed] [Google Scholar]
  19. Le A. X., Bernhard E. J., Holterman M. J., Strub S., Parham P., Lacy E., Engelhard V. H. Cytotoxic T cell responses in HLA-A2.1 transgenic mice. Recognition of HLA alloantigens and utilization of HLA-A2.1 as a restriction element. J Immunol. 1989 Feb 15;142(4):1366–1371. [PubMed] [Google Scholar]
  20. MacDonald H. R., Cerottini J. C., Ryser J. E., Maryanski J. L., Taswell C., Widmer M. B., Brunner K. T. Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol Rev. 1980;51:93–123. doi: 10.1111/j.1600-065x.1980.tb00318.x. [DOI] [PubMed] [Google Scholar]
  21. Matsumura M., Fremont D. H., Peterson P. A., Wilson I. A. Emerging principles for the recognition of peptide antigens by MHC class I molecules. Science. 1992 Aug 14;257(5072):927–934. doi: 10.1126/science.1323878. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Orr H. T., Lopez de Castro J. A., Parham P., Ploegh H. L., Strominger J. L. Comparison of amino acid sequences of two human histocompatibility antigens, HLA-A2 and HLA-B7: location of putative alloantigenic sites. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4395–4399. doi: 10.1073/pnas.76.9.4395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Potter T. A., Bluestone J. A., Rajan T. V. A single amino acid substitution in the alpha 3 domain of an H-2 class I molecule abrogates reactivity with CTL. J Exp Med. 1987 Oct 1;166(4):956–966. doi: 10.1084/jem.166.4.956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ramsdell F., Fowlkes B. J. Engagement of CD4 and CD8 accessory molecules is required for T cell maturation. J Immunol. 1989 Sep 1;143(5):1467–1471. [PubMed] [Google Scholar]
  26. Robey E. A., Fowlkes B. J., Gordon J. W., Kioussis D., von Boehmer H., Ramsdell F., Axel R. Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell. 1991 Jan 11;64(1):99–107. doi: 10.1016/0092-8674(91)90212-h. [DOI] [PubMed] [Google Scholar]
  27. Robey E., Itano A., Fanslow W. C., Fowlkes B. J. Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J Exp Med. 1994 Jun 1;179(6):1997–2004. doi: 10.1084/jem.179.6.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Robey E., Ramsdell F., Elliott J., Raulet D., Kioussis D., Axel R., Fowlkes B. J. Expression of CD4 in transgenic mice alters the specificity of CD8 cells for allogeneic major histocompatibility complex. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):608–612. doi: 10.1073/pnas.88.2.608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Saizawa K., Rojo J., Janeway C. A., Jr Evidence for a physical association of CD4 and the CD3:alpha:beta T-cell receptor. Nature. 1987 Jul 16;328(6127):260–263. doi: 10.1038/328260a0. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Salter R. D., Norment A. M., Chen B. P., Clayberger C., Krensky A. M., Littman D. R., Parham P. Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8. Nature. 1989 Mar 23;338(6213):345–347. doi: 10.1038/338345a0. [DOI] [PubMed] [Google Scholar]
  32. Samberg N. L., Scarlett E. C., Stauss H. J. The alpha 3 domain of major histocompatibility complex class I molecules plays a critical role in cytotoxic T lymphocyte stimulation. Eur J Immunol. 1989 Dec;19(12):2349–2354. doi: 10.1002/eji.1830191225. [DOI] [PubMed] [Google Scholar]
  33. Sanders S. K., Fox R. O., Kavathas P. Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies. J Exp Med. 1991 Aug 1;174(2):371–379. doi: 10.1084/jem.174.2.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sherman L. A., Hesse S. V., Irwin M. J., La Face D., Peterson P. Selecting T cell receptors with high affinity for self-MHC by decreasing the contribution of CD8. Science. 1992 Oct 30;258(5083):815–818. doi: 10.1126/science.1439792. [DOI] [PubMed] [Google Scholar]
  35. Sun J., Leahy D. J., Kavathas P. B. Interaction between CD8 and major histocompatibility complex (MHC) class I mediated by multiple contact surfaces that include the alpha 2 and alpha 3 domains of MHC class I. J Exp Med. 1995 Nov 1;182(5):1275–1280. doi: 10.1084/jem.182.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Teh H. S., Kisielow P., Scott B., Kishi H., Uematsu Y., Blüthmann H., von Boehmer H. Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature. 1988 Sep 15;335(6187):229–233. doi: 10.1038/335229a0. [DOI] [PubMed] [Google Scholar]
  38. Turner J. M., Brodsky M. H., Irving B. A., Levin S. D., Perlmutter R. M., Littman D. R. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell. 1990 Mar 9;60(5):755–765. doi: 10.1016/0092-8674(90)90090-2. [DOI] [PubMed] [Google Scholar]
  39. Vitiello A., Marchesini D., Furze J., Sherman L. A., Chesnut R. W. Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J Exp Med. 1991 Apr 1;173(4):1007–1015. doi: 10.1084/jem.173.4.1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zúiga-Pflücker J. C., Jones L. A., Longo D. L., Kruisbeek A. M. CD8 is required during positive selection of CD4-/CD8+ T cells. J Exp Med. 1990 Feb 1;171(2):427–437. doi: 10.1084/jem.171.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES