Skip to main content
PMC home page
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
. 1995 Apr 25;92(9):4036–4040. doi: 10.1073/pnas.92.9.4036

Differential activation of proliferation and cytotoxicity in human T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered peptide ligand.

P Höllsberg 1, W E Weber 1, F Dangond 1, V Batra 1, A Sette 1, D A Hafler 1
PMCID: PMC42097  PMID: 7732026

Abstract

Human T-cell leukemia virus type I (HTLV-I) gives rise to a neurologic disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the pathogenesis of the disease is unknown, the presence of a remarkably high frequency of Tax-specific, cytotoxic CD8 T cells may suggest a role of these cells in the development of HAM/TSP. Antigen-mediated signaling in a CD8 T-cell clone specific for the Tax(11-19) peptide of HTLV-I was studied using analog peptides substituted in their T-cell receptor contact residues defined by x-ray crystallographic data of the Tax(11-19) peptide in the groove of HLA-A2. CD8 T-cell stimulation with the wild-type peptide antigen led to activation of p56lck kinase activity, interleukin 2 secretion, cytotoxicity, and clonal expansion. A Tax analog peptide with an alanine substitution of the T-cell receptor contact residue tyrosine-15 induced T-cell-mediated cytolysis without activation of interleukin 2 secretion or proliferation. Induction of p56lck kinase activity correlated with T-cell-mediated cytotoxicity, whereas interleukin 2 secretion correlated with [3H]thymidine incorporation and proliferation. Moreover, Tax peptide analogs that activated the tyrosine kinase activity of p56lck could induce unresponsiveness to secondary stimulation with the wild-type peptide. These observations show that a single amino acid substitution in a T-cell receptor contact residue of Tax can differentially signal CD8 T cells and further demonstrate that primary activation has functional consequences for the secondary response of at least some Tax-specific CD8 T cells to HTLV-I-infected target cells.

Full text

PDF
4036

Images in this article

4038Fig. 3
on p.4038
4038Fig. 4
on p.4038

Selected References

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

  1. Caron L., Abraham N., Pawson T., Veillette A. Structural requirements for enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck. Mol Cell Biol. 1992 Jun;12(6):2720–2729. doi: 10.1128/mcb.12.6.2720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  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. Elovaara I., Koenig S., Brewah A. Y., Woods R. M., Lehky T., Jacobson S. High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease. J Exp Med. 1993 Jun 1;177(6):1567–1573. doi: 10.1084/jem.177.6.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  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. 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]
  8. 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]
  9. Germain R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell. 1994 Jan 28;76(2):287–299. doi: 10.1016/0092-8674(94)90336-0. [DOI] [PubMed] [Google Scholar]
  10. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  11. Höllsberg P., Hafler D. A. Seminars in medicine of the Beth Israel Hospital, Boston. Pathogenesis of diseases induced by human lymphotropic virus type I infection. N Engl J Med. 1993 Apr 22;328(16):1173–1182. doi: 10.1056/NEJM199304223281608. [DOI] [PubMed] [Google Scholar]
  12. Höllsberg P., Wucherpfennig K. W., Ausubel L. J., Calvo V., Bierer B. E., Hafler D. A. Characterization of HTLV-I in vivo infected T cell clones. IL-2-independent growth of nontransformed T cells. J Immunol. 1992 May 15;148(10):3256–3263. [PubMed] [Google Scholar]
  13. Jacobson S., Shida H., McFarlin D. E., Fauci A. S., Koenig S. Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I associated neurological disease. Nature. 1990 Nov 15;348(6298):245–248. doi: 10.1038/348245a0. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Koenig S., Woods R. M., Brewah Y. A., Newell A. J., Jones G. M., Boone E., Adelsberger J. W., Baseler M. W., Robinson S. M., Jacobson S. Characterization of MHC class I restricted cytotoxic T cell responses to tax in HTLV-1 infected patients with neurologic disease. J Immunol. 1993 Oct 1;151(7):3874–3883. [PubMed] [Google Scholar]
  16. Luo K., Sefton B. M. Activated lck tyrosine protein kinase stimulates antigen-independent interleukin-2 production in T cells. Mol Cell Biol. 1992 Oct;12(10):4724–4732. doi: 10.1128/mcb.12.10.4724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Madden D. R., Garboczi D. N., Wiley D. C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. 1993 Nov 19;75(4):693–708. doi: 10.1016/0092-8674(93)90490-h. [DOI] [PubMed] [Google Scholar]
  18. Molina T. J., Kishihara K., Siderovski D. P., van Ewijk W., Narendran A., Timms E., Wakeham A., Paige C. J., Hartmann K. U., Veillette A. Profound block in thymocyte development in mice lacking p56lck. Nature. 1992 May 14;357(6374):161–164. doi: 10.1038/357161a0. [DOI] [PubMed] [Google Scholar]
  19. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  20. Osame M., Izumo S., Igata A., Matsumoto M., Matsumoto T., Sonoda S., Tara M., Shibata Y. Blood transfusion and HTLV-I associated myelopathy. Lancet. 1986 Jul 12;2(8498):104–105. doi: 10.1016/s0140-6736(86)91636-3. [DOI] [PubMed] [Google Scholar]
  21. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Rudd C. E., Janssen O., Prasad K. V., Raab M., da Silva A., Telfer J. C., Yamamoto M. src-related protein tyrosine kinases and their surface receptors. Biochim Biophys Acta. 1993 Aug 23;1155(2):239–266. doi: 10.1016/0304-419x(93)90007-y. [DOI] [PubMed] [Google Scholar]
  24. Rudd C. E., Trevillyan J. M., Dasgupta J. D., Wong L. L., Schlossman S. F. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5190–5194. doi: 10.1073/pnas.85.14.5190. [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. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [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. Sette A., Sidney J., del Guercio M. F., Southwood S., Ruppert J., Dahlberg C., Grey H. M., Kubo R. T. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Mol Immunol. 1994 Aug;31(11):813–822. doi: 10.1016/0161-5890(94)90019-1. [DOI] [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. Straus D. B., Weiss A. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell. 1992 Aug 21;70(4):585–593. doi: 10.1016/0092-8674(92)90428-f. [DOI] [PubMed] [Google Scholar]
  31. Veillette A., Horak I. D., Bolen J. B. Post-translational alterations of the tyrosine kinase p56lck in response to activators of protein kinase C. Oncogene Res. 1988 May;2(4):385–401. [PubMed] [Google Scholar]
  32. Weber W. E., Buurman W. A., Vandermeeren M. M., Raus J. C. Activation through CD3 molecule leads to clonal expansion of all human peripheral blood T lymphocytes: functional analysis of clonally expanded cells. J Immunol. 1985 Oct;135(4):2337–2342. [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