Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Sep 15;102(6):1112–1124. doi: 10.1172/JCI3986

CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines.

J J Kim 1, L K Nottingham 1, J I Sin 1, A Tsai 1, L Morrison 1, J Oh 1, K Dang 1, Y Hu 1, K Kazahaya 1, M Bennett 1, T Dentchev 1, D M Wilson 1, A A Chalian 1, J D Boyer 1, M G Agadjanyan 1, D B Weiner 1
PMCID: PMC509094  PMID: 9739045

Abstract

The potential roles of CD8(+) T-cell-induced chemokines in the expansion of immune responses were examined using DNA immunogen constructs as model antigens. We coimmunized cDNA expression cassettes encoding the alpha-chemokines IL-8 and SDF-1alpha and the beta-chemokines MIP-1alpha, RANTES, and MCP-1 along with DNA immunogens and analyzed the resulting antigen-specific immune responses. In a manner more similar to the traditional immune modulatory role of CD4(+) T cells via the expression of Th1 or Th2 cytokines, CD8(+) T cells appeared to play an important role in immune expansion and effector function by producing chemokines. For instance, IL-8 was a strong inducer of CD4(+) T cells, indicated by strong T helper proliferative responses as well as an enhancement of antibody responses. MIP-1alpha had a dramatic effect on antibody responses and modulated the shift of immune responses to a Th2-type response. RANTES coimmunization enhanced the levels of antigen-specific Th1 and cytotoxic T lymphocyte (CTL) responses. Among the chemokines examined, MCP-1 was the most potent activator of CD8(+) CTL activity. The enhanced CTL results are supported by the increased expression of Th1 cytokines IFN-gamma and TNF-alpha and the reduction of IgG1/IgG2a ratio. Our results support that CD8(+) T cells may expand both humoral and cellular responses in vivo through the elaboration of specific chemokines at the peripheral site of infection during the effector stage of the immune response.

Full Text

The Full Text of this article is available as a PDF (434.9 KB).

Selected References

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

  1. Alam R., Forsythe P. A., Stafford S., Lett-Brown M. A., Grant J. A. Macrophage inflammatory protein-1 alpha activates basophils and mast cells. J Exp Med. 1992 Sep 1;176(3):781–786. doi: 10.1084/jem.176.3.781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E., Murphy P. M., Berger E. A. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955–1958. doi: 10.1126/science.272.5270.1955. [DOI] [PubMed] [Google Scholar]
  3. Arend W. P., Dayer J. M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995 Feb;38(2):151–160. doi: 10.1002/art.1780380202. [DOI] [PubMed] [Google Scholar]
  4. Baggiolini M., Dewald B., Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705. doi: 10.1146/annurev.immunol.15.1.675. [DOI] [PubMed] [Google Scholar]
  5. Bleul C. C., Farzan M., Choe H., Parolin C., Clark-Lewis I., Sodroski J., Springer T. A. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996 Aug 29;382(6594):829–833. doi: 10.1038/382829a0. [DOI] [PubMed] [Google Scholar]
  6. Boyer J. D., Ugen K. E., Wang B., Agadjanyan M., Gilbert L., Bagarazzi M. L., Chattergoon M., Frost P., Javadian A., Williams W. V. Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination. Nat Med. 1997 May;3(5):526–532. doi: 10.1038/nm0597-526. [DOI] [PubMed] [Google Scholar]
  7. Carr M. W., Roth S. J., Luther E., Rose S. S., Springer T. A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652–3656. doi: 10.1073/pnas.91.9.3652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Choe H., Farzan M., Sun Y., Sullivan N., Rollins B., Ponath P. D., Wu L., Mackay C. R., LaRosa G., Newman W. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun 28;85(7):1135–1148. doi: 10.1016/s0092-8674(00)81313-6. [DOI] [PubMed] [Google Scholar]
  9. Chuntharapai A., Lee J., Hébert C. A., Kim K. J. Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes. J Immunol. 1994 Dec 15;153(12):5682–5688. [PubMed] [Google Scholar]
  10. Cocchi F., DeVico A. L., Garzino-Demo A., Arya S. K., Gallo R. C., Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995 Dec 15;270(5243):1811–1815. doi: 10.1126/science.270.5243.1811. [DOI] [PubMed] [Google Scholar]
  11. Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661–666. doi: 10.1038/381661a0. [DOI] [PubMed] [Google Scholar]
  12. Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
  13. Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
  14. Iwasaki A., Stiernholm B. J., Chan A. K., Berinstein N. L., Barber B. H. Enhanced CTL responses mediated by plasmid DNA immunogens encoding costimulatory molecules and cytokines. J Immunol. 1997 May 15;158(10):4591–4601. [PubMed] [Google Scholar]
  15. Kim J. J., Ayyavoo V., Bagarazzi M. L., Chattergoon M. A., Dang K., Wang B., Boyer J. D., Weiner D. B. In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol. 1997 Jan 15;158(2):816–826. [PubMed] [Google Scholar]
  16. Kim J. J., Bagarazzi M. L., Trivedi N., Hu Y., Kazahaya K., Wilson D. M., Ciccarelli R., Chattergoon M. A., Dang K., Mahalingam S. Engineering of in vivo immune responses to DNA immunization via codelivery of costimulatory molecule genes. Nat Biotechnol. 1997 Jul;15(7):641–646. doi: 10.1038/nbt0797-641. [DOI] [PubMed] [Google Scholar]
  17. Kim J. J., Trivedi N. N., Nottingham L. K., Morrison L., Tsai A., Hu Y., Mahalingam S., Dang K., Ahn L., Doyle N. K. Modulation of amplitude and direction of in vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens. Eur J Immunol. 1998 Mar;28(3):1089–1103. doi: 10.1002/(SICI)1521-4141(199803)28:03<1089::AID-IMMU1089>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  18. Loetscher M., Geiser T., O'Reilly T., Zwahlen R., Baggiolini M., Moser B. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem. 1994 Jan 7;269(1):232–237. [PubMed] [Google Scholar]
  19. Matsushima K., Baldwin E. T., Mukaida N. Interleukin-8 and MCAF: novel leukocyte recruitment and activating cytokines. Chem Immunol. 1992;51:236–265. [PubMed] [Google Scholar]
  20. Meurer R., Van Riper G., Feeney W., Cunningham P., Hora D., Jr, Springer M. S., MacIntyre D. E., Rosen H. Formation of eosinophilic and monocytic intradermal inflammatory sites in the dog by injection of human RANTES but not human monocyte chemoattractant protein 1, human macrophage inflammatory protein 1 alpha, or human interleukin 8. J Exp Med. 1993 Dec 1;178(6):1913–1921. doi: 10.1084/jem.178.6.1913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mogensen S. C., Virelizier J. L. The interferon-macrophage alliance. Interferon. 1987;8:55–84. [PubMed] [Google Scholar]
  22. Murphy P. M. The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 1994;12:593–633. doi: 10.1146/annurev.iy.12.040194.003113. [DOI] [PubMed] [Google Scholar]
  23. Murphy W. J., Taub D. D., Anver M., Conlon K., Oppenheim J. J., Kelvin D. J., Longo D. L. Human RANTES induces the migration of human T lymphocytes into the peripheral tissues of mice with severe combined immune deficiency. Eur J Immunol. 1994 Aug;24(8):1823–1827. doi: 10.1002/eji.1830240815. [DOI] [PubMed] [Google Scholar]
  24. Oberlin E., Amara A., Bachelerie F., Bessia C., Virelizier J. L., Arenzana-Seisdedos F., Schwartz O., Heard J. M., Clark-Lewis I., Legler D. F. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996 Aug 29;382(6594):833–835. doi: 10.1038/382833a0. [DOI] [PubMed] [Google Scholar]
  25. Qin S., LaRosa G., Campbell J. J., Smith-Heath H., Kassam N., Shi X., Zeng L., Buthcher E. C., Mackay C. R. Expression of monocyte chemoattractant protein-1 and interleukin-8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential. Eur J Immunol. 1996 Mar;26(3):640–647. doi: 10.1002/eji.1830260320. [DOI] [PubMed] [Google Scholar]
  26. Raz E., Watanabe A., Baird S. M., Eisenberg R. A., Parr T. B., Lotz M., Kipps T. J., Carson D. A. Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4523–4527. doi: 10.1073/pnas.90.10.4523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rot A., Krieger M., Brunner T., Bischoff S. C., Schall T. J., Dahinden C. A. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med. 1992 Dec 1;176(6):1489–1495. doi: 10.1084/jem.176.6.1489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schall T. J., Bacon K. B. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol. 1994 Dec;6(6):865–873. doi: 10.1016/0952-7915(94)90006-x. [DOI] [PubMed] [Google Scholar]
  29. Schall T. J., Bacon K., Camp R. D., Kaspari J. W., Goeddel D. V. Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. J Exp Med. 1993 Jun 1;177(6):1821–1826. doi: 10.1084/jem.177.6.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schall T. J., Bacon K., Toy K. J., Goeddel D. V. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature. 1990 Oct 18;347(6294):669–671. doi: 10.1038/347669a0. [DOI] [PubMed] [Google Scholar]
  31. Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
  32. Skerka C., Irving S. G., Bialonski A., Zipfel P. F. Cell type specific expression of members of the IL-8/NAP-1 gene family. Cytokine. 1993 Mar;5(2):112–116. doi: 10.1016/1043-4666(93)90049-b. [DOI] [PubMed] [Google Scholar]
  33. Takahashi H., Nakagawa Y., Pendleton C. D., Houghten R. A., Yokomuro K., Germain R. N., Berzofsky J. A. Induction of broadly cross-reactive cytotoxic T cells recognizing an HIV-1 envelope determinant. Science. 1992 Jan 17;255(5042):333–336. doi: 10.1126/science.1372448. [DOI] [PubMed] [Google Scholar]
  34. Tang D. C., DeVit M., Johnston S. A. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992 Mar 12;356(6365):152–154. doi: 10.1038/356152a0. [DOI] [PubMed] [Google Scholar]
  35. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  36. Tsuji T., Hamajima K., Ishii N., Aoki I., Fukushima J., Xin K. Q., Kawamoto S., Sasaki S., Matsunaga K., Ishigatsubo Y. Immunomodulatory effects of a plasmid expressing B7-2 on human immunodeficiency virus-1-specific cell-mediated immunity induced by a plasmid encoding the viral antigen. Eur J Immunol. 1997 Mar;27(3):782–787. doi: 10.1002/eji.1830270329. [DOI] [PubMed] [Google Scholar]
  37. Ulmer J. B., Donnelly J. J., Parker S. E., Rhodes G. H., Felgner P. L., Dwarki V. J., Gromkowski S. H., Deck R. R., DeWitt C. M., Friedman A. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993 Mar 19;259(5102):1745–1749. doi: 10.1126/science.8456302. [DOI] [PubMed] [Google Scholar]
  38. Vilcek J., Lee T. H. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem. 1991 Apr 25;266(12):7313–7316. [PubMed] [Google Scholar]
  39. Wang B., Ugen K. E., Srikantan V., Agadjanyan M. G., Dang K., Refaeli Y., Sato A. I., Boyer J., Williams W. V., Weiner D. B. Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4156–4160. doi: 10.1073/pnas.90.9.4156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wechsler A. S., Gordon M. C., Dendorfer U., LeClair K. P. Induction of IL-8 expression in T cells uses the CD28 costimulatory pathway. J Immunol. 1994 Sep 15;153(6):2515–2523. [PubMed] [Google Scholar]
  41. Wolff J. A., Malone R. W., Williams P., Chong W., Acsadi G., Jani A., Felgner P. L. Direct gene transfer into mouse muscle in vivo. Science. 1990 Mar 23;247(4949 Pt 1):1465–1468. doi: 10.1126/science.1690918. [DOI] [PubMed] [Google Scholar]
  42. Xiang Z., Ertl H. C. Manipulation of the immune response to a plasmid-encoded viral antigen by coinoculation with plasmids expressing cytokines. Immunity. 1995 Feb;2(2):129–135. doi: 10.1016/s1074-7613(95)80001-8. [DOI] [PubMed] [Google Scholar]
  43. Yocum D. E., Esparza L., Dubry S., Benjamin J. B., Volz R., Scuderi P. Characteristics of tumor necrosis factor production in rheumatoid arthritis. Cell Immunol. 1989 Aug;122(1):131–145. doi: 10.1016/0008-8749(89)90154-8. [DOI] [PubMed] [Google Scholar]

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

RESOURCES