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. 1993 Aug 1;178(2):713–722. doi: 10.1084/jem.178.2.713

T cell receptor interaction with peptide/major histocompatibility complex (MHC) and superantigen/MHC ligands is dominated by antigen

PMCID: PMC2191102  PMID: 8393480

Abstract

While recent evidence strongly suggests that the third complementarity determining regions (CDR3s) of T cell receptors (TCRs) directly contact antigenic peptides bound to major histocompatibility complex (MHC) molecules, the nature of other TCR contact(s) is less clear. Here we probe the extent to which different antigens can affect this interaction by comparing the responses of T cells bearing structurally related TCRs to cytochrome c peptides and staphylococcal enterotoxin A (SEA) presented by 13 mutant antigen-presenting cell (APC) lines. Each APC expresses a class II MHC molecule (I-Ek) with a single substitution of an amino acid residue predicted to be located on the MHC alpha helices and to point "up" towards the TCR. We find that very limited changes (even a single amino acid) in either a CDR3 loop of the TCR or in a contact residue of the antigenic peptide can have a profound effect on relatively distant TCR/MHC interactions. The extent of these effects can be as great as that observed between T cells bearing entirely different TCRs and recognizing different peptides. We also find that superantigen presentation entails a distinct mode of TCR/MHC interaction compared with peptide presentation. These data suggest that TCR/MHC contacts can be made in a variety of ways between the same TCR and MHC, with the final configuration apparently dominated by the antigen. These observations suggest a molecular basis for recent reports in which either peptide analogues or superantigens trigger distinct pathways of T cell activation.

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Selected References

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  1. Ajitkumar P., Geier S. S., Kesari K. V., Borriello F., Nakagawa M., Bluestone J. A., Saper M. A., Wiley D. C., Nathenson S. G. Evidence that multiple residues on both the alpha-helices of the class I MHC molecule are simultaneously recognized by the T cell receptor. Cell. 1988 Jul 1;54(1):47–56. doi: 10.1016/0092-8674(88)90178-x. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. Chothia C., Boswell D. R., Lesk A. M. The outline structure of the T-cell alpha beta receptor. EMBO J. 1988 Dec 1;7(12):3745–3755. doi: 10.1002/j.1460-2075.1988.tb03258.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Magistris M. T., Alexander J., Coggeshall M., Altman A., Gaeta F. C., Grey H. M., Sette A. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell. 1992 Feb 21;68(4):625–634. doi: 10.1016/0092-8674(92)90139-4. [DOI] [PubMed] [Google Scholar]
  6. Dellabona P., Peccoud J., Kappler J., Marrack P., Benoist C., Mathis D. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990 Sep 21;62(6):1115–1121. doi: 10.1016/0092-8674(90)90388-u. [DOI] [PubMed] [Google Scholar]
  7. Dianzani U., Shaw A., al-Ramadi B. K., Kubo R. T., Janeway C. A., Jr Physical association of CD4 with the T cell receptor. J Immunol. 1992 Feb 1;148(3):678–688. [PubMed] [Google Scholar]
  8. Evavold B. D., Allen P. M. Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand. Science. 1991 May 31;252(5010):1308–1310. doi: 10.1126/science.1833816. [DOI] [PubMed] [Google Scholar]
  9. Fink P. J., Matis L. A., McElligott D. L., Bookman M., Hedrick S. M. Correlations between T-cell specificity and the structure of the antigen receptor. Nature. 1986 May 15;321(6067):219–226. doi: 10.1038/321219a0. [DOI] [PubMed] [Google Scholar]
  10. Fox B. S., Chen C., Fraga E., French C. A., Singh B., Schwartz R. H. Functionally distinct agretopic and epitopic sites. Analysis of the dominant T cell determinant of moth and pigeon cytochromes c with the use of synthetic peptide antigens. J Immunol. 1987 Sep 1;139(5):1578–1588. [PubMed] [Google Scholar]
  11. Fox B. S., Chen C., Fraga E., French C. A., Singh B., Schwartz R. H. Functionally distinct agretopic and epitopic sites. Analysis of the dominant T cell determinant of moth and pigeon cytochromes c with the use of synthetic peptide antigens. J Immunol. 1987 Sep 1;139(5):1578–1588. [PubMed] [Google Scholar]
  12. Fremont D. H., Matsumura M., Stura E. A., Peterson P. A., Wilson I. A. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science. 1992 Aug 14;257(5072):919–927. doi: 10.1126/science.1323877. [DOI] [PubMed] [Google Scholar]
  13. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  14. Hansburg D., Fairwell T., Schwartz R. H., Appella E. The T lymphocyte response to cytochrome c. IV. Distinguishable sites on a peptide antigen which affect antigenic strength and memory. J Immunol. 1983 Jul;131(1):319–324. [PubMed] [Google Scholar]
  15. Herman A., Croteau G., Sekaly R. P., Kappler J., Marrack P. HLA-DR alleles differ in their ability to present staphylococcal enterotoxins to T cells. J Exp Med. 1990 Sep 1;172(3):709–717. doi: 10.1084/jem.172.3.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Herman A., Labrecque N., Thibodeau J., Marrack P., Kappler J. W., Sekaly R. P. Identification of the staphylococcal enterotoxin A superantigen binding site in the beta 1 domain of the human histocompatibility antigen HLA-DR. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9954–9958. doi: 10.1073/pnas.88.22.9954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hong S. C., Chelouche A., Lin R. H., Shaywitz D., Braunstein N. S., Glimcher L., Janeway C. A., Jr An MHC interaction site maps to the amino-terminal half of the T cell receptor alpha chain variable domain. Cell. 1992 Jun 12;69(6):999–1009. doi: 10.1016/0092-8674(92)90618-m. [DOI] [PubMed] [Google Scholar]
  18. Jorgensen J. L., Esser U., Fazekas de St Groth B., Reay P. A., Davis M. M. Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics. Nature. 1992 Jan 16;355(6357):224–230. doi: 10.1038/355224a0. [DOI] [PubMed] [Google Scholar]
  19. Karp D. R., Teletski C. L., Scholl P., Geha R., Long E. O. The alpha 1 domain of the HLA-DR molecule is essential for high-affinity binding of the toxic shock syndrome toxin-1. Nature. 1990 Aug 2;346(6283):474–476. doi: 10.1038/346474a0. [DOI] [PubMed] [Google Scholar]
  20. Kunkel T. A., Roberts J. D., Zakour R. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Methods Enzymol. 1987;154:367–382. doi: 10.1016/0076-6879(87)54085-x. [DOI] [PubMed] [Google Scholar]
  21. Lai M. Z., Huang S. Y., Briner T. J., Guillet J. G., Smith J. A., Gefter M. L. T cell receptor gene usage in the response to lambda repressor cI protein. An apparent bias in the usage of a V alpha gene element. J Exp Med. 1988 Sep 1;168(3):1081–1097. doi: 10.1084/jem.168.3.1081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lai M. Z., Jang Y. J., Chen L. K., Gefter M. L. Restricted V-(D)-J junctional regions in the T cell response to lambda-repressor. Identification of residues critical for antigen recognition. J Immunol. 1990 Jun 15;144(12):4851–4856. [PubMed] [Google Scholar]
  23. Lai M. Z., Ross D. T., Guillet J. G., Briner T. J., Gefter M. L., Smith J. A. T lymphocyte response to bacteriophage lambda repressor cI protein. Recognition of the same peptide presented by Ia molecules of different haplotypes. J Immunol. 1987 Dec 15;139(12):3973–3980. [PubMed] [Google Scholar]
  24. Lerner E. A., Matis L. A., Janeway C. A., Jr, Jones P. P., Schwartz R. H., Murphy D. B. Monoclonal antibody against an Ir gene product? J Exp Med. 1980 Oct 1;152(4):1085–1101. doi: 10.1084/jem.152.4.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lin A. Y., Devaux B., Green A., Sagerström C., Elliott J. F., Davis M. M. Expression of T cell antigen receptor heterodimers in a lipid-linked form. Science. 1990 Aug 10;249(4969):677–679. doi: 10.1126/science.1696397. [DOI] [PubMed] [Google Scholar]
  26. Liu H., Lampe M. A., Iregui M. V., Cantor H. Conventional antigen and superantigen may be coupled to distinct and cooperative T-cell activation pathways. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8705–8709. doi: 10.1073/pnas.88.19.8705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lorenz R. G., Allen P. M. Direct evidence for functional self-protein/Ia-molecule complexes in vivo. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5220–5223. doi: 10.1073/pnas.85.14.5220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mariuzza R. A., Poljak R. J. The basics of binding: mechanisms of antigen recognition and mimicry by antibodies. Curr Opin Immunol. 1993 Feb;5(1):50–55. doi: 10.1016/0952-7915(93)90080-c. [DOI] [PubMed] [Google Scholar]
  29. Miller J., Germain R. N. Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain. J Exp Med. 1986 Nov 1;164(5):1478–1489. doi: 10.1084/jem.164.5.1478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nalefski E. A., Kasibhatla S., Rao A. Functional analysis of the antigen binding site on the T cell receptor alpha chain. J Exp Med. 1992 Jun 1;175(6):1553–1563. doi: 10.1084/jem.175.6.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nalefski E. A., Wong J. G., Rao A. Amino acid substitutions in the first complementarity-determining region of a murine T-cell receptor alpha chain affect antigen-major histocompatibility complex recognition. J Biol Chem. 1990 May 25;265(15):8842–8846. [PubMed] [Google Scholar]
  32. O'Rourke A. M., Mescher M. F., Webb S. R. Activation of polyphosphoinositide hydrolysis in T cells by H-2 alloantigen but not MLS determinants. Science. 1990 Jul 13;249(4965):171–174. doi: 10.1126/science.2164711. [DOI] [PubMed] [Google Scholar]
  33. Oyaizu N., Chirmule N., Yagura H., Pahwa R., Good R. A., Pahwa S. Superantigen staphylococcal enterotoxin B-induced T-helper cell activation is independent of CD4 molecules and phosphatidylinositol hydrolysis. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8035–8039. doi: 10.1073/pnas.89.17.8035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  35. Pierres M., Devaux C., Dosseto M., Marchetto S. Clonal analysis of B- and T-cell responses to Ia antigens. I. Topology of epitope regions on I-Ak and I-Ek molecules analyzed with 35 monoclonal alloantibodies. Immunogenetics. 1981 Dec;14(6):481–495. doi: 10.1007/BF00350120. [DOI] [PubMed] [Google Scholar]
  36. Rini J. M., Schulze-Gahmen U., Wilson I. A. Structural evidence for induced fit as a mechanism for antibody-antigen recognition. Science. 1992 Feb 21;255(5047):959–965. doi: 10.1126/science.1546293. [DOI] [PubMed] [Google Scholar]
  37. Rojo J. M., Janeway C. A., Jr The biologic activity of anti-T cell receptor V region monoclonal antibodies is determined by the epitope recognized. J Immunol. 1988 Feb 15;140(4):1081–1088. [PubMed] [Google Scholar]
  38. Samelson L. E., Germain R. N., Schwartz R. H. Monoclonal antibodies against the antigen receptor on a cloned T-cell hybrid. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6972–6976. doi: 10.1073/pnas.80.22.6972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Singer S. J. Intercellular communication and cell-cell adhesion. Science. 1992 Mar 27;255(5052):1671–1677. doi: 10.1126/science.1313187. [DOI] [PubMed] [Google Scholar]
  40. Smilek D. E., Wraith D. C., Hodgkinson S., Dwivedy S., Steinman L., McDevitt H. O. A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9633–9637. doi: 10.1073/pnas.88.21.9633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  42. Watanabe M., Suzuki T., Taniguchi M., Shinohara N. Monoclonal anti-Ia murine alloantibodies crossreactive with the Ia-homologues of other mammalian species including humans. Transplantation. 1983 Dec;36(6):712–718. doi: 10.1097/00007890-198336060-00025. [DOI] [PubMed] [Google Scholar]
  43. Wettstein D. A., Boniface J. J., Reay P. A., Schild H., Davis M. M. Expression of a class II major histocompatibility complex (MHC) heterodimer in a lipid-linked form with enhanced peptide/soluble MHC complex formation at low pH. J Exp Med. 1991 Jul 1;174(1):219–228. doi: 10.1084/jem.174.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. White J., Pullen A., Choi K., Marrack P., Kappler J. W. Antigen recognition properties of mutant V beta 3+ T cell receptors are consistent with an immunoglobulin-like structure for the receptor. J Exp Med. 1993 Jan 1;177(1):119–125. doi: 10.1084/jem.177.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]

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