Abstract
Secondary murine cytotoxic T lymphocyte responses from alloantigen- primed T cells can be induced in vitro by apparently unrelated regimens, such as addition of either concanavalin A (Con A), conditioned medium from Con A stimulated lymphocyte cultures, conditioned medium from secondary mixed lymphocyte cultures (MLC), or stimulator cells sharing only the I-region with the stimulating cells used for primary sensitization. We now report that upon polyclonal (Con A), or antigen-specific (MLC) stimulation, Lyl+ T cells release a factor, which in turn triggers alloantigen primed Ly23+ T cells to proliferation and cytolytic activity. The secondary cytotoxic T lymphocyte inducing factor (SCIF) is produced within 24 h. For its production, an intact protein metabolism, not DNA metabolism, is required. Once induced, the functional activity of SCIF is nonspecific and not H-2 restricted. SCIF allows exponential growth and long-term propagation of cytolytic Ly23+ T cells with specificity to alloantigens used for primary sensitization. SCIF induced activation of alloantigen primed Ly23+ T cells does not require the presence of alloantigens. The results therefore reveal a process by which Lyl+ T-cell-derived nonspecific factor(s) induce autonomously Ly23+ T-cell-mediated, antigen-specific, cytotoxic T lymphocyte responses.
Full Text
The Full Text of this article is available as a PDF (1,006.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alter B. J., Grillot-Courvalin C., Bach M. L., Zier K. S., Sondel P. M., Bach F. H. Secondary cell-mediated lympholysis: importance of H-2 LD and SD factors. J Exp Med. 1976 May 1;143(5):1005–1014. doi: 10.1084/jem.143.5.1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Altman A., Cohen I. R. Cell-free media of mixed lymphocyte cultures augmenting sensitization in vitro of mouse T lymphocytes against allogeneic fibroblasts. Eur J Immunol. 1976 Jul;5(7):437–444. doi: 10.1002/eji.1830050702. [DOI] [PubMed] [Google Scholar]
- Andersson L. C., Häyry P. Generation of T memory cells in one-way mixed lymphocyte culture. I. Selective recovery of activated cells and their reversion to 'secondary' lymphocytes. Scand J Immunol. 1974;3(4):461–469. doi: 10.1111/j.1365-3083.1974.tb01279.x. [DOI] [PubMed] [Google Scholar]
- Bach F. H., Segall M., Zier K. S., Sondel P. M., Alter B. J., Bach M. L. Cell mediated immunity: separation of cells involved in recognitive and destructive phases. Science. 1973 Apr 27;180(4084):403–406. doi: 10.1126/science.180.4084.403. [DOI] [PubMed] [Google Scholar]
- Bach F. H., Voynow N. K. One-way stimulation in mixed leukocyte cultures. Science. 1966 Jul 29;153(3735):545–547. doi: 10.1126/science.153.3735.545. [DOI] [PubMed] [Google Scholar]
- Bonavida B. Concanavalin A-mediated activation of antigen-primed lymphocytes into secondary cytotoxic lymphocytes. J Exp Med. 1977 Feb 1;145(2):293–301. doi: 10.1084/jem.145.2.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cantor H., Boyse E. A. Functional subclasses of T lymphocytes bearing different Ly antigens. II. Cooperation between subclasses of Ly+ cells in the generation of killer activity. J Exp Med. 1975 Jun 1;141(6):1390–1399. doi: 10.1084/jem.141.6.1390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cantor H., Simpson E. Regulation of the immune response by subclasses of T lymphocytes. I. Interactions between pre-killer T cells and regulatory T cells obtained from peripheral lymphoid tissues of mice. Eur J Immunol. 1975 May;5(5):330–336. doi: 10.1002/eji.1830050508. [DOI] [PubMed] [Google Scholar]
- Elliott B. E., Nagy Z., Nabholz M., Pernis B. Antigen recognition by T cells activated in the mixed lymphocyte reaction: specific binding of allogeneic cell material after removal of surface-bound antigen by trypsin. Eur J Immunol. 1977 May;7(5):287–291. doi: 10.1002/eji.1830070509. [DOI] [PubMed] [Google Scholar]
- Finke J. H., Orosz C. G., Battisto J. R. Splenic T-killer cells can be generated by allogeneic thymic cells in conjunction with assisting factor. Nature. 1977 May 26;267(5609):353–354. doi: 10.1038/267353a0. [DOI] [PubMed] [Google Scholar]
- Gillis S., Smith K. A. Long term culture of tumour-specific cytotoxic T cells. Nature. 1977 Jul 14;268(5616):154–156. doi: 10.1038/268154a0. [DOI] [PubMed] [Google Scholar]
- Grollman A. P. Inhibitors of protein biosynthesis. V. Effects of emetine on protein and nucleic acid biosynthesis in HeLa cells. J Biol Chem. 1968 Aug 10;243(15):4089–4094. [PubMed] [Google Scholar]
- Heininger D., Touton M., Chakravarty A. K., Clark W. R. Activation of cytotoxic function in T lymphocytes. J Immunol. 1976 Dec;117(6):2175–2180. [PubMed] [Google Scholar]
- Jandinski J., Cantor H., Tadakuma T., Peavy D. L., Pierce C. W. Separation of helper T cells from suppressor T cells expressing different Ly components. I. Polyclonal activation: suppressor and helper activities are inherent properties of distinct T-cell subclasses. J Exp Med. 1976 Jun 1;143(6):1382–1390. doi: 10.1084/jem.143.6.1382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
- Lafferty K. J., Woolnough J. The origin and mechanism of the allograft reaction. Immunol Rev. 1977;35:231–262. doi: 10.1111/j.1600-065x.1977.tb00241.x. [DOI] [PubMed] [Google Scholar]
- MacDonald H. R., Cerottini J. C., Brunner K. T. Generation of cytotoxic T lymphocytes in vitro. III. Velocity sedimentation studies of the differentiation and fate of effector cells in long-term mixed leukocyte cultures. J Exp Med. 1974 Dec 1;140(6):1511–1521. doi: 10.1084/jem.140.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Müller W. E., Zahn R. K., Bittlingmaier K., Falke D. Inhibition of herpesvirus DNA synthesis by 9-beta-D-arabinofuranosyladenine in cellular and cell-free systems. Ann N Y Acad Sci. 1977 Mar 4;284:34–48. doi: 10.1111/j.1749-6632.1977.tb21935.x. [DOI] [PubMed] [Google Scholar]
- Nagy Z., Elliott B. E., Nabholz M. Specific binding of K- and I-region products of the H-2 complex to activated thymus-derived (T) cells belonging to different Ly subclasses. J Exp Med. 1976 Dec 1;144(6):1545–1553. doi: 10.1084/jem.144.6.1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paetkau V., Mills G., Gerhart S., Monticone V. Proliferation of murine thymic lymphocytes in vitro is mediated by the concanavalin A-induced release of a lymphokine (costimulator). J Immunol. 1976 Oct;117(4):1320–1324. [PubMed] [Google Scholar]
- Peck A. B., Bach F. H. A miniaturized mouse mixed leukocyte culture in serum-free and mouse serum supplemented media. J Immunol Methods. 1973 Oct;3(2):147–163. doi: 10.1016/0022-1759(73)90030-6. [DOI] [PubMed] [Google Scholar]
- Plate J. M. Soluble factors substitute for T-T-cell collaboration in generation of T-killer lymphocytes. Nature. 1976 Mar 25;260(5549):329–331. doi: 10.1038/260329a0. [DOI] [PubMed] [Google Scholar]
- Ryser J. E., Cerottini J. C., Brunner K. T. Generation of cytolytic T lymphocytes in vitro. IX. induction of secondary CTL responses in primary long-term MLC by supernatants from secondary MLC. J Immunol. 1978 Feb;120(2):370–377. [PubMed] [Google Scholar]
- Röllinghoff M., Wagner H. In vitro induction of tumor specific immunity: requirements for T lymphocytes and tumor growth inhibition in vivo. Eur J Immunol. 1973 Aug;3(8):471–476. doi: 10.1002/eji.1830030804. [DOI] [PubMed] [Google Scholar]
- Shaw J., Monticone V., Mills G., Paetkau V. Effects of costimulator on immune responses in vitro. J Immunol. 1978 Jun;120(6):1974–1980. [PubMed] [Google Scholar]
- Thorn R. M., Henney C. S. Studies on the mechanism of lymphocyte-mediated cytolysis. VI. A reappraisal of the requirement for protein synthesis during T cell-mediated lysis. J Immunol. 1976 Jan;116(1):146–149. [PubMed] [Google Scholar]
- Uotila M., Rode H. N., Gordon J. Blastogenic factor: its role in the mixed leukocyte culture reaction. Eur J Immunol. 1978 Feb;8(2):133–138. doi: 10.1002/eji.1830080212. [DOI] [PubMed] [Google Scholar]
- Wagner H., Röllinghoff M. Secondary cytotoxic allograft responses in vitro. II. Differentiation of memory T cells into cytotoxic T lymphocytes in the absence of cell proliferation. Eur J Immunol. 1976 Jan;6(1):15–21. doi: 10.1002/eji.1830060105. [DOI] [PubMed] [Google Scholar]
- Wagner H., Starzinski-Powitz A., Röllinghoff M., Golstein P., Jakob H. T-cell-mediated cytotoxic immune responses to F9 teratocarcinoma cells: cytolytic effector T cells lyse H-2-negative F9 cells and syngeneic spermatogonia. J Exp Med. 1978 Jan 1;147(1):251–264. doi: 10.1084/jem.147.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watanabe T., Fathman C. G., Coutinho A. Clonal growth of T cells in vitro: preliminary attempts to a quantitative approach. Immunol Rev. 1977;35:3–37. doi: 10.1111/j.1600-065x.1977.tb00233.x. [DOI] [PubMed] [Google Scholar]
- Wettstein P. J., Bailey D. W., Mobraaten L. E., Klein J., Frelinger J. A. T-lymphocyte response to H-2 mutants. I. Proliferation is dependent on Ly 1+2+ cells. J Exp Med. 1978 May 1;147(5):1395–1404. doi: 10.1084/jem.147.5.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]