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. 1994 Jun 1;179(6):2005–2015. doi: 10.1084/jem.179.6.2005

Resting and activated T cells display different requirements for CD8 molecules

PMCID: PMC2191512  PMID: 8195722

Abstract

Clonotype-positive (1B2+) T cells from 2C T cell receptor (TCR) transgenic mice were used to define the role of CD8 molecules in the induction phase vs. the effector phase of the primary response to class I alloantigens. Three main findings are reported. First, in the presence of exogenous lymphokines, resting CD8+ 2C cells gave strong proliferative responses to two alloantigens, Ld and Kbm11. In the absence of added lymphokines, however, CD8+ 2C cells responded only to Ld and not to Kbm11; Ld stimulated both interleukin 2 (IL-2) and IL-2 receptor (R) synthesis, whereas Kbm11 elicited only IL-2R synthesis. The primary response of CD8+ 2C cells was thus helper-independent (HI) to Ld but helper-dependent (HD) to Kbm11, presumably reflecting that Ld is a stronger antigen than Kbm11. Second, in contrast to CD8+ cells, CD8- 2C cells mounted only an HD and not an HI response to the strong Ld antigen; conversely, selecting for a minor subset of CD8hi cells enabled 2C cells to mount an HI response to the weak Kbm11 antigen. These findings, together with experiments with heterozygous vs. homozygous stimulator cells, suggest that HI and HD responses reflect differences in the overall avidity of T antigen presenting cell (APC) interaction: high-avidity interaction leads to strong intracellular signaling and an HI response, whereas low-avidity interaction causes weak signaling and an HD response; high-avidity T/APC interaction is heavily dependent on CD8 expression. Third, CD8 expression was found to be less important for CTL activity than for primary proliferative responses. Thus, in contrast to HI proliferative responses, CTL responses of 2C cells to Ld were CD8 independent. However, 2C lysis of Ld targets became strongly CD8 dependent in the presence of limiting doses of anti-TCR (1B2) antibody. Collectively, the data suggest that, both for T cell induction and the expression of effector function, CD8 molecules play a decisive role in augmenting TCR-mediated signaling, either by promoting TCR contact with antigen or delivering kinases (p56lck) to the TCR/CD3 complex, or both.

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Selected References

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  1. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  2. Chan I. T., Limmer A., Louie M. C., Bullock E. D., Fung-Leung W. P., Mak T. W., Loh D. Y. Thymic selection of cytotoxic T cells independent of CD8 alpha-Lck association. Science. 1993 Sep 17;261(5128):1581–1584. doi: 10.1126/science.8372352. [DOI] [PubMed] [Google Scholar]
  3. Doherty P. C., Allan W., Eichelberger M., Carding S. R. Roles of alpha beta and gamma delta T cell subsets in viral immunity. Annu Rev Immunol. 1992;10:123–151. doi: 10.1146/annurev.iy.10.040192.001011. [DOI] [PubMed] [Google Scholar]
  4. Eichmann K., Ehrfeld A., Falk I., Goebel H., Kupsch J., Reimann A., Zgaga-Griesz A., Saizawa K. M., Yachelini P., Tomonari K. Affinity enhancement and transmembrane signaling are associated with distinct epitopes on the CD8 alpha beta heterodimer. J Immunol. 1991 Oct 1;147(7):2075–2081. [PubMed] [Google Scholar]
  5. Fung-Leung W. P., Louie M. C., Limmer A., Ohashi P. S., Ngo K., Chen L., Kawai K., Lacy E., Loh D. Y., Mak T. W. The lack of CD8 alpha cytoplasmic domain resulted in a dramatic decrease in efficiency in thymic maturation but only a moderate reduction in cytotoxic function of CD8+ T lymphocytes. Eur J Immunol. 1993 Nov;23(11):2834–2840. doi: 10.1002/eji.1830231117. [DOI] [PubMed] [Google Scholar]
  6. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  7. Guimezanes A., Schmitt-Verhulst A. M. Inhibition of helper function with anti-Lyt-2 or anti-L3T4 monoclonal antibodies depending on stimulating antigens. Eur J Immunol. 1985 Dec;15(12):1187–1191. doi: 10.1002/eji.1830151209. [DOI] [PubMed] [Google Scholar]
  8. Heath W. R., Kjer-Nielsen L., Hoffmann M. W. Avidity for antigen can influence the helper dependence of CD8+ T lymphocytes. J Immunol. 1993 Dec 1;151(11):5993–6001. [PubMed] [Google Scholar]
  9. Heeg K., Steeg C., Hardt C., Wagner H. Identification of interleukin 2-producing T helper cells within murine Lyt-2+ T lymphocytes: frequency, specificity and clonal segregation from Lyt-2+ precursors of cytotoxic T lymphocytes. Eur J Immunol. 1987 Feb;17(2):229–236. doi: 10.1002/eji.1830170213. [DOI] [PubMed] [Google Scholar]
  10. Kosaka H., Surh C. D., Sprent J. Stimulation of mature unprimed CD8+ T cells by semiprofessional antigen-presenting cells in vivo. J Exp Med. 1992 Nov 1;176(5):1291–1302. doi: 10.1084/jem.176.5.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kranz D. M., Sherman D. H., Sitkovsky M. V., Pasternack M. S., Eisen H. N. Immunoprecipitation of cell surface structures of cloned cytotoxic T lymphocytes by clone-specific antisera. Proc Natl Acad Sci U S A. 1984 Jan;81(2):573–577. doi: 10.1073/pnas.81.2.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kung J. T., Castillo M., Heard P., Kerbacher K., Thomas C. A., 3rd Subpopulations of CD8+ cytotoxic T cell precursors collaborate in the absence of conventional CD4+ helper T cells. J Immunol. 1991 Mar 15;146(6):1783–1790. [PubMed] [Google Scholar]
  13. Kwan-Lim G. E., Ong T., Aosai F., Stauss H., Zamoyska R. Is CD8 dependence a true reflection of TCR affinity for antigen? Int Immunol. 1993 Oct;5(10):1219–1228. doi: 10.1093/intimm/5.10.1219. [DOI] [PubMed] [Google Scholar]
  14. Lane P., Gerhard W., Hubele S., Lanzavecchia A., McConnell F. Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1. Immunology. 1993 Sep;80(1):56–61. [PMC free article] [PubMed] [Google Scholar]
  15. Linsley P. S., Ledbetter J. A. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212. doi: 10.1146/annurev.iy.11.040193.001203. [DOI] [PubMed] [Google Scholar]
  16. Makgoba M. W., Sanders M. E., Shaw S. The CD2-LFA-3 and LFA-1-ICAM pathways: relevance to T-cell recognition. Immunol Today. 1989 Dec;10(12):417–422. doi: 10.1016/0167-5699(89)90039-X. [DOI] [PubMed] [Google Scholar]
  17. Malek T. R., Robb R. J., Shevach E. M. Identification and initial characterization of a rat monoclonal antibody reactive with the murine interleukin 2 receptor-ligand complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5694–5698. doi: 10.1073/pnas.80.18.5694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Maryanski J. L., Pala P., Cerottini J. C., MacDonald H. R. Antigen recognition by H-2-restricted cytolytic T lymphocytes: inhibition of cytolysis by anti-CD8 monoclonal antibodies depends upon both concentration and primary sequence of peptide antigen. Eur J Immunol. 1988 Nov;18(11):1863–1866. doi: 10.1002/eji.1830181135. [DOI] [PubMed] [Google Scholar]
  19. O'Rourke A. M., Mescher M. F. The roles of CD8 in cytotoxic T lymphocyte function. Immunol Today. 1993 Apr;14(4):183–188. doi: 10.1016/0167-5699(93)90283-q. [DOI] [PubMed] [Google Scholar]
  20. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  21. Robinson P. J. Phosphatidylinositol membrane anchors and T-cell activation. Immunol Today. 1991 Jan;12(1):35–41. doi: 10.1016/0167-5699(91)90110-F. [DOI] [PubMed] [Google Scholar]
  22. Sarmiento M., Dialynas D. P., Lancki D. W., Wall K. A., Lorber M. I., Loken M. R., Fitch F. W. Cloned T lymphocytes and monoclonal antibodies as probes for cell surface molecules active in T cell-mediated cytolysis. Immunol Rev. 1982;68:135–169. doi: 10.1111/j.1600-065x.1982.tb01063.x. [DOI] [PubMed] [Google Scholar]
  23. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  24. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  25. Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature. 1988 Sep 15;335(6187):271–274. doi: 10.1038/335271a0. [DOI] [PubMed] [Google Scholar]
  26. Sha W. C., Nelson C. A., Newberry R. D., Pullen J. K., Pease L. R., Russell J. H., Loh D. Y. Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6186–6190. doi: 10.1073/pnas.87.16.6186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sherman L. A., Chattopadhyay S. The molecular basis of allorecognition. Annu Rev Immunol. 1993;11:385–402. doi: 10.1146/annurev.iy.11.040193.002125. [DOI] [PubMed] [Google Scholar]
  28. Sherman L. A., Hesse S. V., Irwin M. J., La Face D., Peterson P. Selecting T cell receptors with high affinity for self-MHC by decreasing the contribution of CD8. Science. 1992 Oct 30;258(5083):815–818. doi: 10.1126/science.1439792. [DOI] [PubMed] [Google Scholar]
  29. Shimonkevitz R., Luescher B., Cerottini J. C., MacDonald H. R. Clonal analysis of cytolytic T lymphocyte-mediated lysis of target cells with inducible antigen expression: correlation between antigen density and requirement for Lyt-2/3 function. J Immunol. 1985 Aug;135(2):892–899. [PubMed] [Google Scholar]
  30. Singer A., Munitz T. I., Golding H., Rosenberg A. S., Mizuochi T. Recognition requirements for the activation, differentiation and function of T-helper cells specific for class I MHC alloantigens. Immunol Rev. 1987 Aug;98:143–170. doi: 10.1111/j.1600-065x.1987.tb00523.x. [DOI] [PubMed] [Google Scholar]
  31. Sprent J., Gao E. K., Webb S. R. T cell reactivity to MHC molecules: immunity versus tolerance. Science. 1990 Jun 15;248(4961):1357–1363. doi: 10.1126/science.1694041. [DOI] [PubMed] [Google Scholar]
  32. Sprent J., Schaefer M. Capacity of purified Lyt-2+ T cells to mount primary proliferative and cytotoxic responses to Ia- tumour cells. Nature. 1986 Aug 7;322(6079):541–544. doi: 10.1038/322541a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sprent J., Schaefer M. Properties of purified T cell subsets. I. In vitro responses to class I vs. class II H-2 alloantigens. J Exp Med. 1985 Dec 1;162(6):2068–2088. doi: 10.1084/jem.162.6.2068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Udaka K., Tsomides T. J., Eisen H. N. A naturally occurring peptide recognized by alloreactive CD8+ cytotoxic T lymphocytes in association with a class I MHC protein. Cell. 1992 Jun 12;69(6):989–998. doi: 10.1016/0092-8674(92)90617-l. [DOI] [PubMed] [Google Scholar]

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