Abstract
The target epitopes, serotype specificity, and cytolytic function of dengue virus-specific T cells may influence their theoretical roles in protection against secondary infection as well as the immunopathogenesis of dengue hemorrhagic fever. To study these factors in an experimental system, we isolated dengue virus-specific CD4+ and CD8+ T-cell clones from dengue-2 virus-immunized BALB/c mice. The T-cell response to dengue virus in this mouse strain was heterogeneous; we identified at least five different CD4+ phenotypes and six different CD8+ phenotypes. Individual T-cell clones recognized epitopes on the dengue virus pre-M, E, NSl/NS2A, and NS3 proteins and were restricted by the I-Ad, I-Ed, Ld, and Kd antigens. Both serotype-specific and serotype-cross-reactive clones were isolated in the CD4+ and CD8+ subsets; among CD8+ clones, those that recognized the dengue virus structural proteins were serotype specific whereas those that recognized the nonstructural proteins were serotype cross-reactive. All of the CD8+ and one of five CD4+ clones lysed dengue virus-infected target cells. Using synthetic peptides, we identified an Ld-restricted epitope on the E protein (residues 331 to 339, SPCKIPFEI) and a Kd-restricted epitope on the NS3 protein (residues 296 to 310, ARGYISTRVEM GEAA). These data parallel previous findings of studies using human dengue virus-specific T-cell clones. This experimental mouse system may be useful for studying the role of the virus serotype and HLA haplotype on T-cell responses after primary dengue virus infection.
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Selected References
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- Boonpucknavig S., Vuttiviroj O., Boonpucknavig V. Infection of young adult mice with dengue virus type 2. Trans R Soc Trop Med Hyg. 1981;75(5):647–653. doi: 10.1016/0035-9203(81)90142-5. [DOI] [PubMed] [Google Scholar]
- Bray M., Lai C. J. Dengue virus premembrane and membrane proteins elicit a protective immune response. Virology. 1991 Nov;185(1):505–508. doi: 10.1016/0042-6822(91)90809-p. [DOI] [PubMed] [Google Scholar]
- Bray M., Zhao B. T., Markoff L., Eckels K. H., Chanock R. M., Lai C. J. Mice immunized with recombinant vaccinia virus expressing dengue 4 virus structural proteins with or without nonstructural protein NS1 are protected against fatal dengue virus encephalitis. J Virol. 1989 Jun;63(6):2853–2856. doi: 10.1128/jvi.63.6.2853-2856.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bukowski J. F., Kurane I., Lai C. J., Bray M., Falgout B., Ennis F. A. Dengue virus-specific cross-reactive CD8+ human cytotoxic T lymphocytes. J Virol. 1989 Dec;63(12):5086–5091. doi: 10.1128/jvi.63.12.5086-5091.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burke D. S., Nisalak A., Johnson D. E., Scott R. M. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg. 1988 Jan;38(1):172–180. doi: 10.4269/ajtmh.1988.38.172. [DOI] [PubMed] [Google Scholar]
- Chaturvedi U. C., Dhawan R., Khanna M., Mathur A. Breakdown of the blood-brain barrier during dengue virus infection of mice. J Gen Virol. 1991 Apr;72(Pt 4):859–866. doi: 10.1099/0022-1317-72-4-859. [DOI] [PubMed] [Google Scholar]
- Clerici M., Lucey D. R., Zajac R. A., Boswell R. N., Gebel H. M., Takahashi H., Berzofsky J. A., Shearer G. M. Detection of cytotoxic T lymphocytes specific for synthetic peptides of gp160 in HIV-seropositive individuals. J Immunol. 1991 Apr 1;146(7):2214–2219. [PubMed] [Google Scholar]
- Delenda C., Staropoli I., Frenkiel M. P., Cabanié L., Deubel V. Analysis of C-terminally truncated dengue 2 and dengue 3 virus envelope glycoproteins: processing in insect cells and immunogenic properties in mice. J Gen Virol. 1994 Jul;75(Pt 7):1569–1578. doi: 10.1099/0022-1317-75-7-1569. [DOI] [PubMed] [Google Scholar]
- Doherty P. C. Cytotoxic T cell effector and memory function in viral immunity. Curr Top Microbiol Immunol. 1996;206:1–14. doi: 10.1007/978-3-642-85208-4_1. [DOI] [PubMed] [Google Scholar]
- Eisenlohr L. C., Yewdell J. W., Bennink J. R. A transient transfection system for identifying biosynthesized proteins processed and presented to class I MHC restricted T lymphocytes. J Immunol Methods. 1992 Sep 18;154(1):131–138. doi: 10.1016/0022-1759(92)90220-N. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Falgout B., Bray M., Schlesinger J. J., Lai C. J. Immunization of mice with recombinant vaccinia virus expressing authentic dengue virus nonstructural protein NS1 protects against lethal dengue virus encephalitis. J Virol. 1990 Sep;64(9):4356–4363. doi: 10.1128/jvi.64.9.4356-4363.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Falgout B., Pethel M., Zhang Y. M., Lai C. J. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol. 1991 May;65(5):2467–2475. doi: 10.1128/jvi.65.5.2467-2475.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Gagnon S. J., Zeng W., Kurane I., Ennis F. A. Identification of two epitopes on the dengue 4 virus capsid protein recognized by a serotype-specific and a panel of serotype-cross-reactive human CD4+ cytotoxic T-lymphocyte clones. J Virol. 1996 Jan;70(1):141–147. doi: 10.1128/jvi.70.1.141-147.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gonzalez-Gay M. A., Zanelli E., Krco C. J., Nabozny G. H., Hanson J., Griffiths M. M., Luthra H. S., David C. S. Polymorphism of the MHC class II Eb gene determines the protection against collagen-induced arthritis. Immunogenetics. 1995;42(1):35–40. doi: 10.1007/BF00164985. [DOI] [PubMed] [Google Scholar]
- Green S., Kurane I., Edelman R., Tacket C. O., Eckels K. H., Vaughn D. W., Hoke C. H., Jr, Ennis F. A. Dengue virus-specific human CD4+ T-lymphocyte responses in a recipient of an experimental live-attenuated dengue virus type 1 vaccine: bulk culture proliferation, clonal analysis, and precursor frequency determination. J Virol. 1993 Oct;67(10):5962–5967. doi: 10.1128/jvi.67.10.5962-5967.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guzmán M. G., Kouri G. P., Bravo J., Soler M., Vazquez S., Morier L. Dengue hemorrhagic fever in Cuba, 1981: a retrospective seroepidemiologic study. Am J Trop Med Hyg. 1990 Feb;42(2):179–184. doi: 10.4269/ajtmh.1990.42.179. [DOI] [PubMed] [Google Scholar]
- Halstead S. B. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis. 1989 May-Jun;11 (Suppl 4):S830–S839. doi: 10.1093/clinids/11.supplement_4.s830. [DOI] [PubMed] [Google Scholar]
- Halstead S. B. Pathogenesis of dengue: challenges to molecular biology. Science. 1988 Jan 29;239(4839):476–481. doi: 10.1126/science.3277268. [DOI] [PubMed] [Google Scholar]
- Halstead S. B. The XXth century dengue pandemic: need for surveillance and research. World Health Stat Q. 1992;45(2-3):292–298. [PubMed] [Google Scholar]
- Hosmalin A., Clerici M., Houghten R., Pendleton C. D., Flexner C., Lucey D. R., Moss B., Germain R. N., Shearer G. M., Berzofsky J. A. An epitope in human immunodeficiency virus 1 reverse transcriptase recognized by both mouse and human cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2344–2348. doi: 10.1073/pnas.87.6.2344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurane I., Brinton M. A., Samson A. L., Ennis F. A. Dengue virus-specific, human CD4+ CD8- cytotoxic T-cell clones: multiple patterns of virus cross-reactivity recognized by NS3-specific T-cell clones. J Virol. 1991 Apr;65(4):1823–1828. doi: 10.1128/jvi.65.4.1823-1828.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurane I., Ennis F. E. Immunity and immunopathology in dengue virus infections. Semin Immunol. 1992 Apr;4(2):121–127. [PubMed] [Google Scholar]
- Kurane I., Innis B. L., Nimmannitya S., Nisalak A., Meager A., Janus J., Ennis F. A. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest. 1991 Nov;88(5):1473–1480. doi: 10.1172/JCI115457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurane I., Innis B. L., Nisalak A., Hoke C., Nimmannitya S., Meager A., Ennis F. A. Human T cell responses to dengue virus antigens. Proliferative responses and interferon gamma production. J Clin Invest. 1989 Feb;83(2):506–513. doi: 10.1172/JCI113911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurane I., Meager A., Ennis F. A. Dengue virus-specific human T cell clones. Serotype crossreactive proliferation, interferon gamma production, and cytotoxic activity. J Exp Med. 1989 Sep 1;170(3):763–775. doi: 10.1084/jem.170.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurane I., Okamoto Y., Dai L. C., Zeng L. L., Brinton M. A., Ennis F. A. Flavivirus-cross-reactive, HLA-DR15-restricted epitope on NS3 recognized by human CD4+ CD8- cytotoxic T lymphocyte clones. J Gen Virol. 1995 Sep;76(Pt 9):2243–2249. doi: 10.1099/0022-1317-76-9-2243. [DOI] [PubMed] [Google Scholar]
- Kurane I., Rothman A. L., Livingston P. G., Green S., Gagnon S. J., Janus J., Innis B. L., Nimmannitya S., Nisalak A., Ennis F. A. Immunopathologic mechanisms of dengue hemorrhagic fever and dengue shock syndrome. Arch Virol Suppl. 1994;9:59–64. doi: 10.1007/978-3-7091-9326-6_7. [DOI] [PubMed] [Google Scholar]
- Kutubuddin M., Kolaskar A. S., Galande S., Gore M. M., Ghosh S. N., Banerjee K. Recognition of helper T cell epitopes in envelope (E) glycoprotein of Japanese encephalitis, west Nile and Dengue viruses. Mol Immunol. 1991 Jan-Feb;28(1-2):149–154. doi: 10.1016/0161-5890(91)90098-5. [DOI] [PubMed] [Google Scholar]
- Livingston P. G., Kurane I., Dai L. C., Okamoto Y., Lai C. J., Men R., Karaki S., Takiguchi M., Ennis F. A. Dengue virus-specific, HLA-B35-restricted, human CD8+ cytotoxic T lymphocyte (CTL) clones. Recognition of NS3 amino acids 500 to 508 by CTL clones of two different serotype specificities. J Immunol. 1995 Feb 1;154(3):1287–1295. [PubMed] [Google Scholar]
- Livingston P. G., Kurane I., Lai C. J., Bray M., Ennis F. A. Recognition of envelope protein by dengue virus serotype-specific human CD4+ CD8- cytotoxic T-cell clones. J Virol. 1994 May;68(5):3283–3288. doi: 10.1128/jvi.68.5.3283-3288.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lukacher A. E., Morrison L. A., Braciale V. L., Malissen B., Braciale T. J. Expression of specific cytolytic activity by H-2I region-restricted, influenza virus-specific T lymphocyte clones. J Exp Med. 1985 Jul 1;162(1):171–187. doi: 10.1084/jem.162.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Margulies D. H., Evans G. A., Ozato K., Camerini-Otero R. D., Tanaka K., Appella E., Seidman J. G. Expression of H-2Dd and H-2Ld mouse major histocompatibility antigen genes in L cells after DNA-mediated gene transfer. J Immunol. 1983 Jan;130(1):463–470. [PubMed] [Google Scholar]
- Men R. H., Bray M., Lai C. J. Carboxy-terminally truncated dengue virus envelope glycoproteins expressed on the cell surface and secreted extracellularly exhibit increased immunogenicity in mice. J Virol. 1991 Mar;65(3):1400–1407. doi: 10.1128/jvi.65.3.1400-1407.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Monath T. P. Dengue: the risk to developed and developing countries. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2395–2400. doi: 10.1073/pnas.91.7.2395. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morens D. M. Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis. 1994 Sep;19(3):500–512. doi: 10.1093/clinids/19.3.500. [DOI] [PubMed] [Google Scholar]
- Morrison D. C., Ryan J. L. Bacterial endotoxins and host immune responses. Adv Immunol. 1979;28:293–450. doi: 10.1016/s0065-2776(08)60802-0. [DOI] [PubMed] [Google Scholar]
- Morrison L. A., Braciale V. L., Braciale T. J. Antigen form influences induction and frequency of influenza-specific class I and class II MHC-restricted cytolytic T lymphocytes. J Immunol. 1988 Jul 15;141(2):363–368. [PubMed] [Google Scholar]
- Osatomi K., Sumiyoshi H. Complete nucleotide sequence of dengue type 3 virus genome RNA. Virology. 1990 Jun;176(2):643–647. doi: 10.1016/0042-6822(90)90037-r. [DOI] [PubMed] [Google Scholar]
- Roehrig J. T., Johnson A. J., Hunt A. R., Beaty B. J., Mathews J. H. Enhancement of the antibody response to flavivirus B-cell epitopes by using homologous or heterologous T-cell epitopes. J Virol. 1992 Jun;66(6):3385–3390. doi: 10.1128/jvi.66.6.3385-3390.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rothman A. L., Kurane I., Lai C. J., Bray M., Falgout B., Men R., Ennis F. A. Dengue virus protein recognition by virus-specific murine CD8+ cytotoxic T lymphocytes. J Virol. 1993 Feb;67(2):801–806. doi: 10.1128/jvi.67.2.801-806.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rothman A. L., Kurane I., Zhang Y. M., Lai C. J., Ennis F. A. Dengue virus-specific murine T-lymphocyte proliferation: serotype specificity and response to recombinant viral proteins. J Virol. 1989 Jun;63(6):2486–2491. doi: 10.1128/jvi.63.6.2486-2491.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sangkawibha N., Rojanasuphot S., Ahandrik S., Viriyapongse S., Jatanasen S., Salitul V., Phanthumachinda B., Halstead S. B. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol. 1984 Nov;120(5):653–669. doi: 10.1093/oxfordjournals.aje.a113932. [DOI] [PubMed] [Google Scholar]
- Schlesinger J. J., Brandriss M. W., Walsh E. E. Protection of mice against dengue 2 virus encephalitis by immunization with the dengue 2 virus non-structural glycoprotein NS1. J Gen Virol. 1987 Mar;68(Pt 3):853–857. doi: 10.1099/0022-1317-68-3-853. [DOI] [PubMed] [Google Scholar]
- Shirai M., Okada H., Nishioka M., Akatsuka T., Wychowski C., Houghten R., Pendleton C. D., Feinstone S. M., Berzofsky J. A. An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans. J Virol. 1994 May;68(5):3334–3342. doi: 10.1128/jvi.68.5.3334-3342.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takahashi H., Cohen J., Hosmalin A., Cease K. B., Houghten R., Cornette J. L., DeLisi C., Moss B., Germain R. N., Berzofsky J. A. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. doi: 10.1073/pnas.85.9.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhao B. T., Prince G., Horswood R., Eckels K., Summers P., Chanock R., Lai C. J. Expression of dengue virus structural proteins and nonstructural protein NS1 by a recombinant vaccinia virus. J Virol. 1987 Dec;61(12):4019–4022. doi: 10.1128/jvi.61.12.4019-4022.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]