T cell activation determined by T cell receptor number and tunable thresholds

Science

Volumn 273, Issue 5271, 1996, Pages 104-106

  Viola, Antonella ^a   Lanzavecchia, Antonio ^a  

^a BASEL INSTITUTE FOR IMMUNOLOGY   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

T LYMPHOCYTE RECEPTOR;

ANTIGEN PRESENTATION; ARTICLE; HUMAN; HUMAN CELL; LIGAND BINDING; LYMPHOCYTE ACTIVATION; PRIORITY JOURNAL; T LYMPHOCYTE;

EID: 0030057218     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.273.5271.104     Document Type: Article

References (33)

1. A. Townsend et al., Cell 62, 285 (1990); B. P. Babbitt, P. M. Allen, G. Matsueda, E. Haber, E. R. Unanue, Nature 317, 359 (1985); M. M. Davis and P. J. Bjorkman, ibid. 334, 395 (1988).
2. A. Townsend et al., Cell 62, 285 (1990); B. P. Babbitt, P. M. Allen, G. Matsueda, E. Haber, E. R. Unanue, Nature 317, 359 (1985); M. M. Davis and P. J. Bjorkman, ibid. 334, 395 (1988).
3. A. Townsend et al., Cell 62, 285 (1990); B. P. Babbitt, P. M. Allen, G. Matsueda, E. Haber, E. R. Unanue, Nature 317, 359 (1985); M. M. Davis and P. J. Bjorkman, ibid. 334, 395 (1988).
4. J. Kappler et al., Science 244, 811 (1989): J. Thibodeau et al., ibid. 266, 1874 (1994).
5. J. Kappler et al., Science 244, 811 (1989): J. Thibodeau et al., ibid. 266, 1874 (1994).
6. W. J. M. Tax, H. W. Willems, P. P. M. Reekers, P. J. A. Capel, R. A. P. Koene, Nature 304, 445 (1983); J. Kaye, S. Porcelli, J. Tite, B. Jones, C. A. Janeway, J. Exp. Med. 158, 836 (1983); S. C. Meuer et al., ibid., p. 988.
7. W. J. M. Tax, H. W. Willems, P. P. M. Reekers, P. J. A. Capel, R. A. P. Koene, Nature 304, 445 (1983); J. Kaye, S. Porcelli, J. Tite, B. Jones, C. A. Janeway, J. Exp. Med. 158, 836 (1983); S. C. Meuer et al., ibid., p. 988.
8. W. J. M. Tax, H. W. Willems, P. P. M. Reekers, P. J. A. Capel, R. A. P. Koene, Nature 304, 445 (1983); J. Kaye, S. Porcelli, J. Tite, B. Jones, C. A. Janeway, J. Exp. Med. 158, 836 (1983); S. C. Meuer et al., ibid., p. 988.
9. K. Inaba and R. M. Steinman, J. Exp. Med. 160, 1717 (1984); M. Luqman and K. Bottomly, J. Immunol. 149, 2300 (1992); M. Croft, D. D. Duncan, S. L. Swain, J. Exp. Med. 176, 1431 (1992)
10. K. Inaba and R. M. Steinman, J. Exp. Med. 160, 1717 (1984); M. Luqman and K. Bottomly, J. Immunol. 149, 2300 (1992); M. Croft, D. D. Duncan, S. L. Swain, J. Exp. Med. 176, 1431 (1992)
11. K. Inaba and R. M. Steinman, J. Exp. Med. 160, 1717 (1984); M. Luqman and K. Bottomly, J. Immunol. 149, 2300 (1992); M. Croft, D. D. Duncan, S. L. Swain, J. Exp. Med. 176, 1431 (1992)
12. S. Valitutti, S. Müller, M. Cella, E. Padovan, A. Lanzavecchia, Nature 375, 148 (1995).
13. 5 APCs were placed in 200 μl of RPMI 1640 and 5% fetal bovine serum in 96 U-bottom microplates, centrifuged to allow conjugate formation, and incubated at 37°C for 5 hours. TCR down-regulation was measured by indirect immunofluorescence (5) with an excess of OCTR1 followed by a second antibody. The data were calculated using the mean fluorescence value of the cell population (SE, <0.5). IFN-γ production was measured as described (5). The data represent the mean of triplicate wells (SD, <10%).
14. K. Matsui et al., Science 254, 1788 (1991); S. Weber, A. Traunecker, F. Oliveri, W. Gerhard, K. Karjalainen, Nature 356, 793 (1992); K. Matsui, J. J. Boniface, P. Steffner, P. A. Reay, M. M. Davis, Proc. Natl. Acad. Sci. U.S.A. 91, 12862 (1994); M. Corr et al., Science 265, 946 (1994).
15. K. Matsui et al., Science 254, 1788 (1991); S. Weber, A. Traunecker, F. Oliveri, W. Gerhard, K. Karjalainen, Nature 356, 793 (1992); K. Matsui, J. J. Boniface, P. Steffner, P. A. Reay, M. M. Davis, Proc. Natl. Acad. Sci. U.S.A. 91, 12862 (1994); M. Corr et al., Science 265, 946 (1994).
16. K. Matsui et al., Science 254, 1788 (1991); S. Weber, A. Traunecker, F. Oliveri, W. Gerhard, K. Karjalainen, Nature 356, 793 (1992); K. Matsui, J. J. Boniface, P. Steffner, P. A. Reay, M. M. Davis, Proc. Natl. Acad. Sci. U.S.A. 91, 12862 (1994); M. Corr et al., Science 265, 946 (1994).
17. K. Matsui et al., Science 254, 1788 (1991); S. Weber, A. Traunecker, F. Oliveri, W. Gerhard, K. Karjalainen, Nature 356, 793 (1992); K. Matsui, J. J. Boniface, P. Steffner, P. A. Reay, M. M. Davis, Proc. Natl. Acad. Sci. U.S.A. 91, 12862 (1994); M. Corr et al., Science 265, 946 (1994).
18. For stimulation by peptide-MHC or TSST-MHC, the data fit a logarithmic curve, y = a + b(log x), which indicates that serial triggering is optimal at low ligand density and becomes less effective as the number of complexes increases. For stimulation by anti-CD3, the data fit a linear curve, y = ax (where a < 1), which indicates that the process has the same efficiency over the range of antibody concentrations tested. The latter conclusion was confirmed in experiments in which the same EBV-B cells used for peptide or TSST presentation were pulsed with known amounts of a bispecific anti-CD3-anti-MHC class II antibody (A. Viola, unpublished data).
19. + T cell clones and correlates with a lower capacity of antibody to recruit CD4 in the triggered TCR complex, as shown by decreased CD4 down-regulation (A. Viola, in preparation). At subthreshold numbers of TCRs, no IFN-γ production was detected by a sensitive enzyme-linked immunosorbent assay (ELISA), whereas above the threshold the IFN-γ production rapidly reached a plateau. Because the clones used were CD28 , the threshold was not affected by the type of APC or by the presence or absence of costimulation. Nor was the threshold affected by addition of interleukin-12, which doubled the amount of IFN-γ produced.
20. β5.2) did not react with TSST.
21. i increase is sustained for ≥30 min.
22. A. Lanzavecchia, in The Tolerance Workshop 1986, P. Matzinger et al., Eds. (Roche, Basel, 1986), pp. 293-298. T cell clones retained small numbers of TCRs for as long as 5 to 8 days after stimulation.
23. T cells from a DR11-restricted T cell clone (KS140) specific for the tetanus toxin 830-843 peptide were stimulated at 1:1 ratio with mitomycin C-treated autologous EBV-B cells pulsed with different concentrations of peptide. After 3 days, CD3 concentrations were measured and the cells were tested for their capacity to proliferate in response to fresh EBV-B cells pulsed with different concentrations of peptide.
24. + THP1. Separately, T cell clones were conjugated with EBV-B cells pulsed with various concentrations of TSST in the presence or absence of CTLA4-immunoglobulin (Ig) fusion protein (19). All long-term T cell clones expressed very little or no CD28. Comparable results were obtained when THP1 was used for presentation of both TSST and antibody.
25. H. Fischer et al., J. Immunol. 148, 1993 (1992); N. Bhardwaj, J. W. Young, A. J. Nisanian, J. Baggers, R. M. Steinman, J. Exp. Med. 178, 633 (1993).
26. H. Fischer et al., J. Immunol. 148, 1993 (1992); N. Bhardwaj, J. W. Young, A. J. Nisanian, J. Baggers, R. M. Steinman, J. Exp. Med. 178, 633 (1993).
27. G. Schönrich et al., Cell 65, 293 (1991); I. Ferber et al., Science 263, 674 (1994).
28. G. Schönrich et al., Cell 65, 293 (1991); I. Ferber et al., Science 263, 674 (1994).
29. P. Panina-Bordignon, X. T. Fu, A. Lanzavecchia, R. W. Karr, J. Exp. Med. 176, 1779 (1992).
30. E. Roosnek and A. Lanzavecchia, ibid. 170, 297 (1989).
31. C. Döhring, L. Angman, G. Spagnoli, A. Lanzavecchia, Int. J. Cancer 57, 754 (1994).
32. A. Lanzavecchia, Nature 314, 537 (1985).
33. We thank K. Karjalainen, G. De Libero, and S. Valitutti for critical reading and comments, and M. Dessing for help in flow cytometry. A.L. is associate professor of immunology at the University of Genova, Genova, Italy. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche, Basel, Switzerland.