Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Jul 1;184(1):149–157. doi: 10.1084/jem.184.1.149

Partial signaling by CD8+ T cells in response to antagonist ligands

PMCID: PMC2192672  PMID: 8691128

Abstract

Structural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8+ T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern of early TCR-associated tyrosine phosphorylation events in CD4+ T cells. We have therefore directly examined proximal TCR signaling in a CD8+ T cell line in response to various related ligands. TCR engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR- associated tyrosine phosphorylation events as seen with CD4+ cells, including accumulation of both the p21 and p23 forms of phosphorylated zeta, phosphorylation of CD3 epsilon, and association of phosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, gamma interferon secretion, interleukin-2 receptor alpha upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta without net phosphorylation of CD3 epsilon, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR- dependent phosphorylation events in CD8+ T cells as first observed in CD4+ cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellular biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes.

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. Alberola-Ila J., Forbush K. A., Seger R., Krebs E. G., Perlmutter R. M. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature. 1995 Feb 16;373(6515):620–623. doi: 10.1038/373620a0. [DOI] [PubMed] [Google Scholar]
  2. Allen H., Wraith D., Pala P., Askonas B., Flavell R. A. Domain interactions of H-2 class I antigens alter cytotoxic T-cell recognition sites. Nature. 1984 May 17;309(5965):279–281. doi: 10.1038/309279a0. [DOI] [PubMed] [Google Scholar]
  3. Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
  4. Chan A. C., Desai D. M., Weiss A. The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annu Rev Immunol. 1994;12:555–592. doi: 10.1146/annurev.iy.12.040194.003011. [DOI] [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. 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]
  7. 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]
  8. Evavold B. D., Sloan-Lancaster J., Hsu B. L., Allen P. M. Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides. J Immunol. 1993 Apr 15;150(8 Pt 1):3131–3140. [PubMed] [Google Scholar]
  9. 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]
  10. Hogquist K. A., Jameson S. C., Bevan M. J. Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells. Immunity. 1995 Jul;3(1):79–86. doi: 10.1016/1074-7613(95)90160-4. [DOI] [PubMed] [Google Scholar]
  11. Hogquist K. A., Jameson S. C., Heath W. R., Howard J. L., Bevan M. J., Carbone F. R. T cell receptor antagonist peptides induce positive selection. Cell. 1994 Jan 14;76(1):17–27. doi: 10.1016/0092-8674(94)90169-4. [DOI] [PubMed] [Google Scholar]
  12. Höllsberg P., Weber W. E., Dangond F., Batra V., Sette A., Hafler D. A. Differential activation of proliferation and cytotoxicity in human T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered peptide ligand. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):4036–4040. doi: 10.1073/pnas.92.9.4036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jameson S. C., Bevan M. J. Dissection of major histocompatibility complex (MHC) and T cell receptor contact residues in a Kb-restricted ovalbumin peptide and an assessment of the predictive power of MHC-binding motifs. Eur J Immunol. 1992 Oct;22(10):2663–2667. doi: 10.1002/eji.1830221028. [DOI] [PubMed] [Google Scholar]
  14. Jameson S. C., Bevan M. J. T cell receptor antagonists and partial agonists. Immunity. 1995 Jan;2(1):1–11. doi: 10.1016/1074-7613(95)90074-8. [DOI] [PubMed] [Google Scholar]
  15. Jameson S. C., Carbone F. R., Bevan M. J. Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells. J Exp Med. 1993 Jun 1;177(6):1541–1550. doi: 10.1084/jem.177.6.1541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jameson S. C., Hogquist K. A., Bevan M. J. Specificity and flexibility in thymic selection. Nature. 1994 Jun 30;369(6483):750–752. doi: 10.1038/369750a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  18. Ljunggren H. G., Kärre K. Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J Exp Med. 1985 Dec 1;162(6):1745–1759. doi: 10.1084/jem.162.6.1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Madrenas J., Germain R. N. Variant TCR ligands: new insights into the molecular basis of antigen-dependent signal transduction and T-cell activation. Semin Immunol. 1996 Apr;8(2):83–101. doi: 10.1006/smim.1996.0011. [DOI] [PubMed] [Google Scholar]
  20. Madrenas J., Wange R. L., Wang J. L., Isakov N., Samelson L. E., Germain R. N. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science. 1995 Jan 27;267(5197):515–518. doi: 10.1126/science.7824949. [DOI] [PubMed] [Google Scholar]
  21. Matsumura M., Saito Y., Jackson M. R., Song E. S., Peterson P. A. In vitro peptide binding to soluble empty class I major histocompatibility complex molecules isolated from transfected Drosophila melanogaster cells. J Biol Chem. 1992 Nov 25;267(33):23589–23595. [PubMed] [Google Scholar]
  22. Qian D., Griswold-Prenner I., Rosner M. R., Fitch F. W. Multiple components of the T cell antigen receptor complex become tyrosine-phosphorylated upon activation. J Biol Chem. 1993 Feb 25;268(6):4488–4493. [PubMed] [Google Scholar]
  23. 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]
  24. Reis e Sousa C., Germain R. N. Major histocompatibility complex class I presentation of peptides derived from soluble exogenous antigen by a subset of cells engaged in phagocytosis. J Exp Med. 1995 Sep 1;182(3):841–851. doi: 10.1084/jem.182.3.841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Schumacher T. N., De Bruijn M. L., Vernie L. N., Kast W. M., Melief C. J., Neefjes J. J., Ploegh H. L. Peptide selection by MHC class I molecules. Nature. 1991 Apr 25;350(6320):703–706. doi: 10.1038/350703a0. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Shi J., Miller R. A. Differential tyrosine-specific protein phosphorylation in mouse T lymphocyte subsets. Effect of age. J Immunol. 1993 Jul 15;151(2):730–739. [PubMed] [Google Scholar]
  29. 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]
  30. Sloan-Lancaster J., Shaw A. S., Rothbard J. B., Allen P. M. Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy. Cell. 1994 Dec 2;79(5):913–922. doi: 10.1016/0092-8674(94)90080-9. [DOI] [PubMed] [Google Scholar]
  31. Snoke K., Alexander J., Franco A., Smith L., Brawley J. V., Concannon P., Grey H. M., Sette A., Wentworth P. The inhibition of different T cell lines specific for the same antigen with TCR antagonist peptides. J Immunol. 1993 Dec 15;151(12):6815–6821. [PubMed] [Google Scholar]
  32. Swan K. A., Alberola-Ila J., Gross J. A., Appleby M. W., Forbush K. A., Thomas J. F., Perlmutter R. M. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J. 1995 Jan 16;14(2):276–285. doi: 10.1002/j.1460-2075.1995.tb07001.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tite J. P., Sloan A., Janeway C. A., Jr The role of L3T4 in T cell activation: L3T4 may be both an Ia-binding protein and a receptor that transduces a negative signal. J Mol Cell Immunol. 1986;2(4):179–190. [PubMed] [Google Scholar]
  34. Weiss A., Littman D. R. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. doi: 10.1016/0092-8674(94)90334-4. [DOI] [PubMed] [Google Scholar]
  35. Wiest D. L., Yuan L., Jefferson J., Benveniste P., Tsokos M., Klausner R. D., Glimcher L. H., Samelson L. E., Singer A. Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J Exp Med. 1993 Nov 1;178(5):1701–1712. doi: 10.1084/jem.178.5.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Williams O., Tanaka Y., Bix M., Murdjeva M., Littman D. R., Kioussis D. Inhibition of thymocyte negative selection by T cell receptor antagonist peptides. Eur J Immunol. 1996 Mar;26(3):532–538. doi: 10.1002/eji.1830260305. [DOI] [PubMed] [Google Scholar]
  37. 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]

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

RESOURCES