Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Aug 15;90(16):7608–7612. doi: 10.1073/pnas.90.16.7608

Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I.

T J Briner 1, M C Kuo 1, K M Keating 1, B L Rogers 1, J L Greenstein 1
PMCID: PMC47191  PMID: 8356062

Abstract

T cells control the majority of antigen-specific immune responses. Therefore, influencing the activation of the T-cell response in order to modify immune responsiveness is an obvious therapeutic goal. We have used a mouse model of response to Fel d I, the major cat protein allergen in humans, to explore the ability of peptides derived from Fel d I to inhibit T-cell-dependent immune responses to the peptides themselves and to larger polypeptides. T cells from B6CBAF1 mice respond to the Fel d I peptide IPC-2 after challenge with IPC-2. However, subcutaneous tolerization with IPC-2 prevents this response as measured by production of interleukins 2 and 4 and interferon gamma. Fel d I immunization of B6D2F1 mice results in T-cell responses primarily to one peptide derived from Fel d I. Injecting this peptide in soluble form inhibits T-cell activation (as measured by interleukin 2 production) and antibody production in Fel d I-primed animals when they are subsequently challenged with peptide in adjuvant. Most of the cat-allergic human T-cell response to Fel d I is specific for two peptides on one of its two chains. Immunization of B6CBAF1 mice with recombinant Fel d I chain 1 results in T-cell responses to the same peptides. Subcutaneous administration of these two peptides, which contain some, but not all, of the T-cell epitopes from Fel d I chain I, decreases the T-cell response to the entire recombinant Fel d I chain 1. The ability to tolerize T-cell responses with subcutaneous injections suggests a practical approach to treating human diseases with peptides containing T-cell epitopes.

Full text

PDF
7608

Images in this article

Selected References

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

  1. 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]
  2. Baniyash M., Eshhar Z. Inhibition of IgE binding to mast cells and basophils by monoclonal antibodies to murine IgE. Eur J Immunol. 1984 Sep;14(9):799–807. doi: 10.1002/eji.1830140907. [DOI] [PubMed] [Google Scholar]
  3. Burkly L. C., Lo D., Kanagawa O., Brinster R. L., Flavell R. A. T-cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC class II I-E. Nature. 1989 Nov 30;342(6249):564–566. doi: 10.1038/342564a0. [DOI] [PubMed] [Google Scholar]
  4. Burstein H. J., Shea C. M., Abbas A. K. Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-gamma-producing (Th1) cells. J Immunol. 1992 Jun 15;148(12):3687–3691. [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. Chapman M. D., Aalberse R. C., Brown M. J., Platts-Mills T. A. Monoclonal antibodies to the major feline allergen Fel d I. II. Single step affinity purification of Fel d I, N-terminal sequence analysis, and development of a sensitive two-site immunoassay to assess Fel d I exposure. J Immunol. 1988 Feb 1;140(3):812–818. [PubMed] [Google Scholar]
  7. DIETRICH F. M., WEIGLE W. O. IMMUNOLOGIC UNRESPONSIVENESS TO HETEROLOGOUS SERUM PROTEINS INDUCED IN ADULT MICE AND TRANSFER OF THE UNRESPONSIVE STATE. J Immunol. 1964 Feb;92:167–172. [PubMed] [Google Scholar]
  8. De Wit D., Van Mechelen M., Ryelandt M., Figueiredo A. C., Abramowicz D., Goldman M., Bazin H., Urbain J., Leo O. The injection of deaggregated gamma globulins in adult mice induces antigen-specific unresponsiveness of T helper type 1 but not type 2 lymphocytes. J Exp Med. 1992 Jan 1;175(1):9–14. doi: 10.1084/jem.175.1.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gammon G., Sercarz E. How some T cells escape tolerance induction. Nature. 1989 Nov 9;342(6246):183–185. doi: 10.1038/342183a0. [DOI] [PubMed] [Google Scholar]
  10. Gilbert K. M., Hoang K. D., Weigle W. O. Th1 and Th2 clones differ in their response to a tolerogenic signal. J Immunol. 1990 Mar 15;144(6):2063–2071. [PubMed] [Google Scholar]
  11. Guillet J. G., Lai M. Z., Briner T. J., Smith J. A., Gefter M. L. Interaction of peptide antigens and class II major histocompatibility complex antigens. Nature. 1986 Nov 20;324(6094):260–262. doi: 10.1038/324260a0. [DOI] [PubMed] [Google Scholar]
  12. Hämmerling G. J., Schönrich G., Momburg F., Auphan N., Malissen M., Malissen B., Schmitt-Verhulst A. M., Arnold B. Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissue-specific expression of a foreign MHC class I antigen. Immunol Rev. 1991 Aug;122:47–67. doi: 10.1111/j.1600-065x.1991.tb00596.x. [DOI] [PubMed] [Google Scholar]
  13. Ishizaka K., Ishizaka T., Hornbrook M. M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity wth gamma-E-globulin antibody. J Immunol. 1966 Dec;97(6):840–853. [PubMed] [Google Scholar]
  14. Janeway C. A., Jr Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1–13. doi: 10.1101/sqb.1989.054.01.003. [DOI] [PubMed] [Google Scholar]
  15. Jenkins M. K., Burrell E., Ashwell J. D. Antigen presentation by resting B cells. Effectiveness at inducing T cell proliferation is determined by costimulatory signals, not T cell receptor occupancy. J Immunol. 1990 Mar 1;144(5):1585–1590. [PubMed] [Google Scholar]
  16. Jenkins M. K., Chen C. A., Jung G., Mueller D. L., Schwartz R. H. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J Immunol. 1990 Jan 1;144(1):16–22. [PubMed] [Google Scholar]
  17. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jenkins M. K., Taylor P. S., Norton S. D., Urdahl K. B. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991 Oct 15;147(8):2461–2466. [PubMed] [Google Scholar]
  19. Karvelas M., Nossal G. J. Memory cell generation ablated by soluble protein antigen by means of effects on T- and B-lymphocyte compartments. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3150–3154. doi: 10.1073/pnas.89.7.3150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lamb J. R., Skidmore B. J., Green N., Chiller J. M., Feldmann M. Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med. 1983 May 1;157(5):1434–1447. doi: 10.1084/jem.157.5.1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Linsley P. S., Clark E. A., Ledbetter J. A. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5031–5035. doi: 10.1073/pnas.87.13.5031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Miller J. F., Morahan G., Allison J., Hoffmann M. A transgenic approach to the study of peripheral T-cell tolerance. Immunol Rev. 1991 Aug;122:103–116. doi: 10.1111/j.1600-065x.1991.tb00599.x. [DOI] [PubMed] [Google Scholar]
  23. Monroe J. G., Lowy A., Granstein R. D., Greene M. I. Studies of immune responsiveness and unresponsiveness to the p-azobenzenearsonate (ABA) hapten. Immunol Rev. 1984 Aug;80:103–131. doi: 10.1111/j.1600-065x.1984.tb00497.x. [DOI] [PubMed] [Google Scholar]
  24. Morgenstern J. P., Griffith I. J., Brauer A. W., Rogers B. L., Bond J. F., Chapman M. D., Kuo M. C. Amino acid sequence of Fel dI, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9690–9694. doi: 10.1073/pnas.88.21.9690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mueller D. L., Chiodetti L., Bacon P. A., Schwartz R. H. Clonal anergy blocks the response to IL-4, as well as the production of IL-2, in dual-producing T helper cell clones. J Immunol. 1991 Dec 15;147(12):4118–4125. [PubMed] [Google Scholar]
  26. Ohman J. L., Jr, Lowell F. C., Bloch K. J. Allergens of mammalian origin. III. Properties of a major feline allergen. J Immunol. 1974 Dec;113(6):1668–1677. [PubMed] [Google Scholar]
  27. Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
  28. 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]
  29. Rogers B. L., Morgenstern J. P., Garman R. D., Bond J. F., Kuo M. C. Recombinant Fel d.I: Expression, purification, IgE binding and reaction with cat-allergic human T cells. Mol Immunol. 1993 Apr;30(6):559–568. doi: 10.1016/0161-5890(93)90030-f. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Zanders E. D., Lamb J. R., Feldmann M., Green N., Beverley P. C. Tolerance of T-cell clones is associated with membrane antigen changes. Nature. 1983 Jun 16;303(5918):625–627. doi: 10.1038/303625a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES