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. 1995 Jul 1;182(1):261–266. doi: 10.1084/jem.182.1.261

T cell priming versus T cell tolerance induced by synthetic peptides

PMCID: PMC2192100  PMID: 7540654

Abstract

It is well known that synthetic peptides are able to both induce and tolerize T cells. We have examined the parameters leading either to priming or tolerance of CD8+ cytotoxic T lymphocytes (CTL) in vivo with a major histocompatibility complex class I (H-2 Db) binding peptide derived from the glycoprotein (GP aa33-41) of lymphocytic choriomeningitis virus (LCMV). By varying dose, route, and frequency of LCMV GP peptide application, we found that a single local subcutaneous injection of 50-500 micrograms peptide emulsified in incomplete Freund's adjuvant protected mice against LCMV infection, whereas repetitive and systemic intraperitoneal application of the same dose caused tolerance of LCMV-specific CTL. The peptide-induced tolerance was transient in euthymic mice but permanent in thymectomized mice. These findings are relevant for a selective use of peptides as a therapeutic approach: peptide-induced priming of T cells for vaccination and peptide-mediated T cell tolerance for intervention in immunopathologies and autoimmune diseases.

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Selected References

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  1. Aichele P., Hengartner H., Zinkernagel R. M., Schulz M. Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide. J Exp Med. 1990 May 1;171(5):1815–1820. doi: 10.1084/jem.171.5.1815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aichele P., Kyburz D., Ohashi P. S., Odermatt B., Zinkernagel R. M., Hengartner H., Pircher H. Peptide-induced T-cell tolerance to prevent autoimmune diabetes in a transgenic mouse model. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):444–448. doi: 10.1073/pnas.91.2.444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnon R., Horwitz R. J. Synthetic peptides as vaccines. Curr Opin Immunol. 1992 Aug;4(4):449–453. doi: 10.1016/s0952-7915(06)80037-3. [DOI] [PubMed] [Google Scholar]
  4. Battegay M., Cooper S., Althage A., Bänziger J., Hengartner H., Zinkernagel R. M. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J Virol Methods. 1991 Jun;33(1-2):191–198. doi: 10.1016/0166-0934(91)90018-u. [DOI] [PubMed] [Google Scholar]
  5. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987 Oct 8;329(6139):512–518. doi: 10.1038/329512a0. [DOI] [PubMed] [Google Scholar]
  6. Bretscher P., Cohn M. A theory of self-nonself discrimination. Science. 1970 Sep 11;169(3950):1042–1049. doi: 10.1126/science.169.3950.1042. [DOI] [PubMed] [Google Scholar]
  7. Briner T. J., Kuo M. C., Keating K. M., Rogers B. L., Greenstein J. L. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7608–7612. doi: 10.1073/pnas.90.16.7608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carbone F. R., Bevan M. J. Induction of ovalbumin-specific cytotoxic T cells by in vivo peptide immunization. J Exp Med. 1989 Mar 1;169(3):603–612. doi: 10.1084/jem.169.3.603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chiller J. M., Habicht G. S., Weigle W. O. Kinetic differences in unresponsiveness of thymus and bone marrow cells. Science. 1971 Feb 26;171(3973):813–815. doi: 10.1126/science.171.3973.813. [DOI] [PubMed] [Google Scholar]
  10. Clayton J. P., Gammon G. M., Ando D. G., Kono D. H., Hood L., Sercarz E. E. Peptide-specific prevention of experimental allergic encephalomyelitis. Neonatal tolerance induced to the dominant T cell determinant of myelin basic protein. J Exp Med. 1989 May 1;169(5):1681–1691. doi: 10.1084/jem.169.5.1681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Critchfield J. M., Racke M. K., Zúiga-Pflücker J. C., Cannella B., Raine C. S., Goverman J., Lenardo M. J. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science. 1994 Feb 25;263(5150):1139–1143. doi: 10.1126/science.7509084. [DOI] [PubMed] [Google Scholar]
  12. DRESSER D. W. Specific inhibition of antibody production. II. Paralysis induced in adult mice by small quantities of protein antigen. Immunology. 1962 May;5:378–388. [PMC free article] [PubMed] [Google Scholar]
  13. Deres K., Schild H., Wiesmüller K. H., Jung G., Rammensee H. G. In vivo priming of virus-specific cytotoxic T lymphocytes with synthetic lipopeptide vaccine. Nature. 1989 Nov 30;342(6249):561–564. doi: 10.1038/342561a0. [DOI] [PubMed] [Google Scholar]
  14. Falk K., Rötzschke O., Rammensee H. G. Cellular peptide composition governed by major histocompatibility complex class I molecules. Nature. 1990 Nov 15;348(6298):248–251. doi: 10.1038/348248a0. [DOI] [PubMed] [Google Scholar]
  15. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  16. Feltkamp M. C., Smits H. L., Vierboom M. P., Minnaar R. P., de Jongh B. M., Drijfhout J. W., ter Schegget J., Melief C. J., Kast W. M. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol. 1993 Sep;23(9):2242–2249. doi: 10.1002/eji.1830230929. [DOI] [PubMed] [Google Scholar]
  17. Gao X. M., Zheng B., Liew F. Y., Brett S., Tite J. Priming of influenza virus-specific cytotoxic T lymphocytes vivo by short synthetic peptides. J Immunol. 1991 Nov 15;147(10):3268–3273. [PubMed] [Google Scholar]
  18. Gaur A., Wiers B., Liu A., Rothbard J., Fathman C. G. Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. Science. 1992 Nov 27;258(5087):1491–1494. doi: 10.1126/science.1279812. [DOI] [PubMed] [Google Scholar]
  19. Good M. F., Maloy W. L., Lunde M. N., Margalit H., Cornette J. L., Smith G. L., Moss B., Miller L. H., Berzofsky J. A. Construction of synthetic immunogen: use of new T-helper epitope on malaria circumsporozoite protein. Science. 1987 Feb 27;235(4792):1059–1062. doi: 10.1126/science.2434994. [DOI] [PubMed] [Google Scholar]
  20. Hoyne G. F., O'Hehir R. E., Wraith D. C., Thomas W. R., Lamb J. R. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice. J Exp Med. 1993 Nov 1;178(5):1783–1788. doi: 10.1084/jem.178.5.1783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jenkins M. K. The ups and downs of T cell costimulation. Immunity. 1994 Sep;1(6):443–446. doi: 10.1016/1074-7613(94)90086-8. [DOI] [PubMed] [Google Scholar]
  22. Kast W. M., Offringa R., Peters P. J., Voordouw A. C., Meloen R. H., van der Eb A. J., Melief C. J. Eradication of adenovirus E1-induced tumors by E1A-specific cytotoxic T lymphocytes. Cell. 1989 Nov 17;59(4):603–614. doi: 10.1016/0092-8674(89)90006-8. [DOI] [PubMed] [Google Scholar]
  23. Kast W. M., Roux L., Curren J., Blom H. J., Voordouw A. C., Meloen R. H., Kolakofsky D., Melief C. J. Protection against lethal Sendai virus infection by in vivo priming of virus-specific cytotoxic T lymphocytes with a free synthetic peptide. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2283–2287. doi: 10.1073/pnas.88.6.2283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kaufman D. L., Clare-Salzler M., Tian J., Forsthuber T., Ting G. S., Robinson P., Atkinson M. A., Sercarz E. E., Tobin A. J., Lehmann P. V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993 Nov 4;366(6450):69–72. doi: 10.1038/366069a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kearney E. R., Pape K. A., Loh D. Y., Jenkins M. K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity. 1994 Jul;1(4):327–339. doi: 10.1016/1074-7613(94)90084-1. [DOI] [PubMed] [Google Scholar]
  26. Kyburz D., Aichele P., Speiser D. E., Hengartner H., Zinkernagel R. M., Pircher H. T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides. Eur J Immunol. 1993 Aug;23(8):1956–1962. doi: 10.1002/eji.1830230834. [DOI] [PubMed] [Google Scholar]
  27. Lafferty K. J., Cunningham A. J. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975 Feb;53(1):27–42. doi: 10.1038/icb.1975.3. [DOI] [PubMed] [Google Scholar]
  28. Lenardo M. J. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature. 1991 Oct 31;353(6347):858–861. doi: 10.1038/353858a0. [DOI] [PubMed] [Google Scholar]
  29. MITCHISON N. A. INDUCTION OF IMMUNOLOGICAL PARALYSIS IN TWO ZONES OF DOSAGE. Proc R Soc Lond B Biol Sci. 1964 Dec 15;161:275–292. doi: 10.1098/rspb.1964.0093. [DOI] [PubMed] [Google Scholar]
  30. Mamalaki C., Tanaka Y., Corbella P., Chandler P., Simpson E., Kioussis D. T cell deletion follows chronic antigen specific T cell activation in vivo. Int Immunol. 1993 Oct;5(10):1285–1292. doi: 10.1093/intimm/5.10.1285. [DOI] [PubMed] [Google Scholar]
  31. Maryanski J. L., Pala P., Corradin G., Jordan B. R., Cerottini J. C. H-2-restricted cytolytic T cells specific for HLA can recognize a synthetic HLA peptide. Nature. 1986 Dec 11;324(6097):578–579. doi: 10.1038/324578a0. [DOI] [PubMed] [Google Scholar]
  32. Metzler B., Wraith D. C. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int Immunol. 1993 Sep;5(9):1159–1165. doi: 10.1093/intimm/5.9.1159. [DOI] [PubMed] [Google Scholar]
  33. Milich D. R., McLachlan A., Thornton G. B., Hughes J. L. Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature. 1987 Oct 8;329(6139):547–549. doi: 10.1038/329547a0. [DOI] [PubMed] [Google Scholar]
  34. Moskophidis D., Lechner F., Pircher H., Zinkernagel R. M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993 Apr 22;362(6422):758–761. doi: 10.1038/362758a0. [DOI] [PubMed] [Google Scholar]
  35. Oki A., Sercarz E. T cell tolerance studied at the level of antigenic determinants. I. Latent reactivity to lysozyme peptides that lack suppressogenic epitopes can be revealed in lysozyme-tolerant mice. J Exp Med. 1985 May 1;161(5):897–911. doi: 10.1084/jem.161.5.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
  37. Ria F., Chan B. M., Scherer M. T., Smith J. A., Gefter M. L. Immunological activity of covalently linked T-cell epitopes. Nature. 1990 Jan 25;343(6256):381–383. doi: 10.1038/343381a0. [DOI] [PubMed] [Google Scholar]
  38. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  39. Rötzschke O., Falk K., Deres K., Schild H., Norda M., Metzger J., Jung G., Rammensee H. G. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature. 1990 Nov 15;348(6298):252–254. doi: 10.1038/348252a0. [DOI] [PubMed] [Google Scholar]
  40. Schulz M., Aichele P., Vollenweider M., Bobe F. W., Cardinaux F., Hengartner H., Zinkernagel R. M. Major histocompatibility complex--dependent T cell epitopes of lymphocytic choriomeningitis virus nucleoprotein and their protective capacity against viral disease. Eur J Immunol. 1989 Sep;19(9):1657–1667. doi: 10.1002/eji.1830190921. [DOI] [PubMed] [Google Scholar]
  41. Schulz M., Zinkernagel R. M., Hengartner H. Peptide-induced antiviral protection by cytotoxic T cells. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):991–993. doi: 10.1073/pnas.88.3.991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tisch R., McDevitt H. O. Antigen-specific immunotherapy: is it a real possibility to combat T-cell-mediated autoimmunity? Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):437–438. doi: 10.1073/pnas.91.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tisch R., Yang X. D., Singer S. M., Liblau R. S., Fugger L., McDevitt H. O. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993 Nov 4;366(6450):72–75. doi: 10.1038/366072a0. [DOI] [PubMed] [Google Scholar]
  44. Townsend A. R., Gotch F. M., Davey J. Cytotoxic T cells recognize fragments of the influenza nucleoprotein. Cell. 1985 Sep;42(2):457–467. doi: 10.1016/0092-8674(85)90103-5. [DOI] [PubMed] [Google Scholar]
  45. Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  46. Vidard L., Colarusso L. J., Benacerraf B. Specific T-cell tolerance may be preceded by a primary response. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5627–5631. doi: 10.1073/pnas.91.12.5627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Warren H. S., Vogel F. R., Chedid L. A. Current status of immunological adjuvants. Annu Rev Immunol. 1986;4:369–388. doi: 10.1146/annurev.iy.04.040186.002101. [DOI] [PubMed] [Google Scholar]
  48. Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
  49. Wolowczuk I., Auriault C., Bossus M., Boulanger D., Gras-Masse H., Mazingue C., Pierce R. J., Grezel D., Reid G. D., Tartar A. Antigenicity and immunogenicity of a multiple peptidic construction of the Schistosoma mansoni Sm-28 GST antigen in rat, mouse, and monkey. 1. Partial protection of Fischer rat after active immunization. J Immunol. 1991 Mar 15;146(6):1987–1995. [PubMed] [Google Scholar]
  50. Zinkernagel R. M., Leist T., Hengartner H., Althage A. Susceptibility to lymphocytic choriomeningitis virus isolates correlates directly with early and high cytotoxic T cell activity, as well as with footpad swelling reaction, and all three are regulated by H-2D. J Exp Med. 1985 Dec 1;162(6):2125–2141. doi: 10.1084/jem.162.6.2125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

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