Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Nov 1;98(9):2001–2007. doi: 10.1172/JCI119004

F(c)gammaRI-targeted fusion proteins result in efficient presentation by human monocytes of antigenic and antagonist T cell epitopes.

C Liu 1, J Goldstein 1, R F Graziano 1, J He 1, J K O'Shea 1, Y Deo 1, P M Guyre 1
PMCID: PMC507643  PMID: 8903318

Abstract

A major challenge for using native or modified T cell epitopes to induce or suppress immunity relates to poor localization of peptides to antigen presenting cells (APCs) in vivo. In this study, we demonstrate enhanced presentation of antigenic and antagonistic peptides by targeting them to the type I Fc receptor for IgG (F(c)gammaRI, CD64) on human monocytes. A Th epitope of tetanus toxoid, TT830, and the antagonistic peptide for TT830, TT833S, were genetically grafted into the constant region of the heavy chain of the humanized anti-CD64 mAb 22 and expressed as monovalent fusion proteins, Fab22-TT830 and Fab22-TT833S. These CD64-targeted peptides were up to 1,000- and 100-fold more efficient than the parent peptides for T cell stimulation and antagonism, respectively, suggesting that such fusion proteins could effectively increase the delivery of peptides to APCs in vivo. Moreover, the F(c)gammaRI-targeted antagonistic peptide inhibited proliferation of TT830-specific T cells even when APCs were first pulsed with native peptide, a situation comparable with that which would be encountered in vivo when attempting to ameliorate an autoimmune response. These data suggest that targeted presentation of antagonistic peptides could lead to promising Ag-specific therapies for T cell-mediated autoimmune diseases.

Full Text

The Full Text of this article is available as a PDF (246.6 KB).

Selected References

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

  1. 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]
  2. Berzofsky J. A. Epitope selection and design of synthetic vaccines. Molecular approaches to enhancing immunogenicity and cross-reactivity of engineered vaccines. Ann N Y Acad Sci. 1993 Aug 12;690:256–264. doi: 10.1111/j.1749-6632.1993.tb44014.x. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Evavold B. D., Sloan-Lancaster J., Allen P. M. Antagonism of superantigen-stimulated helper T-cell clones and hybridomas by altered peptide ligand. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2300–2304. doi: 10.1073/pnas.91.6.2300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Evavold B. D., Sloan-Lancaster J., Allen P. M. Tickling the TCR: selective T-cell functions stimulated by altered peptide ligands. Immunol Today. 1993 Dec;14(12):602–609. doi: 10.1016/0167-5699(93)90200-5. [DOI] [PubMed] [Google Scholar]
  7. Fanger N. A., Wardwell K., Shen L., Tedder T. F., Guyre P. M. Type I (CD64) and type II (CD32) Fc gamma receptor-mediated phagocytosis by human blood dendritic cells. J Immunol. 1996 Jul 15;157(2):541–548. [PubMed] [Google Scholar]
  8. Franco A., Southwood S., Arrhenius T., Kuchroo V. K., Grey H. M., Sette A., Ishioka G. Y. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. Eur J Immunol. 1994 Apr;24(4):940–946. doi: 10.1002/eji.1830240424. [DOI] [PubMed] [Google Scholar]
  9. Gosselin E. J., Brown M. F., Anderson C. L., Zipf T. F., Guyre P. M. The monoclonal antibody 41H16 detects the Leu 4 responder form of human Fc gamma RII. J Immunol. 1990 Mar 1;144(5):1817–1822. [PubMed] [Google Scholar]
  10. Gosselin E. J., Wardwell K., Gosselin D. R., Alter N., Fisher J. L., Guyre P. M. Enhanced antigen presentation using human Fc gamma receptor (monocyte/macrophage)-specific immunogens. J Immunol. 1992 Dec 1;149(11):3477–3481. [PubMed] [Google Scholar]
  11. Graziano R. F., Tempest P. R., White P., Keler T., Deo Y., Ghebremariam H., Coleman K., Pfefferkorn L. C., Fanger M. W., Guyre P. M. Construction and characterization of a humanized anti-gamma-Ig receptor type I (Fc gamma RI) monoclonal antibody. J Immunol. 1995 Nov 15;155(10):4996–5002. [PubMed] [Google Scholar]
  12. Guyre P. M., Graziano R. F., Vance B. A., Morganelli P. M., Fanger M. W. Monoclonal antibodies that bind to distinct epitopes on Fc gamma RI are able to trigger receptor function. J Immunol. 1989 Sep 1;143(5):1650–1655. [PubMed] [Google Scholar]
  13. Heijnen I. A., van Vugt M. J., Fanger N. A., Graziano R. F., de Wit T. P., Hofhuis F. M., Guyre P. M., Capel P. J., Verbeek J. S., van de Winkel J. G. Antigen targeting to myeloid-specific human Fc gamma RI/CD64 triggers enhanced antibody responses in transgenic mice. J Clin Invest. 1996 Jan 15;97(2):331–338. doi: 10.1172/JCI118420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kuchroo V. K., Greer J. M., Kaul D., Ishioka G., Franco A., Sette A., Sobel R. A., Lees M. B. A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. J Immunol. 1994 Oct 1;153(7):3326–3336. [PubMed] [Google Scholar]
  15. Mentzer S. J., Guyre P. M., Burakoff S. J., Faller D. V. Spontaneous aggregation as a mechanism for human monocyte purification. Cell Immunol. 1986 Sep;101(2):312–319. doi: 10.1016/0008-8749(86)90144-9. [DOI] [PubMed] [Google Scholar]
  16. Nanda N. K., Sercarz E. E. Induction of anti-self-immunity to cure cancer. Cell. 1995 Jul 14;82(1):13–17. doi: 10.1016/0092-8674(95)90047-0. [DOI] [PubMed] [Google Scholar]
  17. Nicholson L. B., Greer J. M., Sobel R. A., Lees M. B., Kuchroo V. K. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity. 1995 Oct;3(4):397–405. doi: 10.1016/1074-7613(95)90169-8. [DOI] [PubMed] [Google Scholar]
  18. Paul W. E., Seder R. A. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. doi: 10.1016/0092-8674(94)90332-8. [DOI] [PubMed] [Google Scholar]
  19. Pfeiffer C., Stein J., Southwood S., Ketelaar H., Sette A., Bottomly K. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995 Apr 1;181(4):1569–1574. doi: 10.1084/jem.181.4.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Racioppi L., Ronchese F., Matis L. A., Germain R. N. Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling. J Exp Med. 1993 Apr 1;177(4):1047–1060. doi: 10.1084/jem.177.4.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ruppert J., Alexander J., Snoke K., Coggeshall M., Herbert E., McKenzie D., Grey H. M., Sette A. Effect of T-cell receptor antagonism on interaction between T cells and antigen-presenting cells and on T-cell signaling events. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2671–2675. doi: 10.1073/pnas.90.7.2671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ruppert J., Franco A., Alexander J., Snoke K., Ishioka G. Y., Page D. M., Hedrick S. M., Adorini L., Grey H. M., Sette A. MHC blocking peptides and T-cell receptor antagonists: novel paths to selective immunosuppression? Chem Immunol. 1995;60:61–78. [PubMed] [Google Scholar]
  23. Sercarz E. E., Lehmann P. V., Ametani A., Benichou G., Miller A., Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729–766. doi: 10.1146/annurev.iy.11.040193.003501. [DOI] [PubMed] [Google Scholar]
  24. Sette A., Alexander J., Ruppert J., Snoke K., Franco A., Ishioka G., Grey H. M. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Annu Rev Immunol. 1994;12:413–431. doi: 10.1146/annurev.iy.12.040194.002213. [DOI] [PubMed] [Google Scholar]
  25. Sloan-Lancaster J., Evavold B. D., Allen P. M. Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature. 1993 May 13;363(6425):156–159. doi: 10.1038/363156a0. [DOI] [PubMed] [Google Scholar]
  26. Sloan-Lancaster J., Evavold B. D., Allen P. M. Th2 cell clonal anergy as a consequence of partial activation. J Exp Med. 1994 Oct 1;180(4):1195–1205. doi: 10.1084/jem.180.4.1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Valmori D., Sabbatini A., Lanzavecchia A., Corradin G., Matricardi P. M. Functional analysis of two tetanus toxin universal T cell epitopes in their interaction with DR1101 and DR1104 alleles. J Immunol. 1994 Mar 15;152(6):2921–2929. [PubMed] [Google Scholar]
  28. Valone F. H., Kaufman P. A., Guyre P. M., Lewis L. D., Memoli V., Deo Y., Graziano R., Fisher J. L., Meyer L., Mrozek-Orlowski M. Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu. J Clin Oncol. 1995 Sep;13(9):2281–2292. doi: 10.1200/JCO.1995.13.9.2281. [DOI] [PubMed] [Google Scholar]
  29. Windhagen A., Scholz C., Höllsberg P., Fukaura H., Sette A., Hafler D. A. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity. 1995 Apr;2(4):373–380. doi: 10.1016/1074-7613(95)90145-0. [DOI] [PubMed] [Google Scholar]
  30. Zaghouani H., Steinman R., Nonacs R., Shah H., Gerhard W., Bona C. Presentation of a viral T cell epitope expressed in the CDR3 region of a self immunoglobulin molecule. Science. 1993 Jan 8;259(5092):224–227. doi: 10.1126/science.7678469. [DOI] [PubMed] [Google Scholar]
  31. Zanetti M. Antigenized antibodies. Nature. 1992 Jan 30;355(6359):476–477. doi: 10.1038/355476a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES