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4. Multiple cytolytic mechanisms displayed by activated human peripheral blood T cell subsets

Author

Mark Smyth, Norihisa, Y., and Ortaldo, J. R.

Subjects
Immunology, Immunology and Allergy
Abstract

It has been proposed that CTL-mediated cytotoxicity may involve multiple lytic mechanisms. We have examined both the antibody-redirected cytolytic potential and the direct cytotoxicity of purified human peripheral blood high buoyant density CD4+ and CD8+ T cells activated with IL-2 and anti-CD3 mAb. TNF-sensitive and TNF-resistant targets and various metabolic inhibitors were used to compare the antibody-redirected cytotoxicity of T cell subsets and discern the role of potential lytic mediators. In a 4-h assay against several different nitrophenyl-modified targets, the heteroconjugated antibody (anti-CD3-anti-nitrophenyl) redirected cytolytic potential of 72-h activated CD4+ T cells was inhibited by the continuous presence of actinomycin D, cycloheximide, and EGTA, but not mitomycin C, cyclosporin A, or cholera toxin (CT). Conversely, only CT and EGTA inhibited the antibody-redirected cytolytic potential of activated CD8+ T cells. Despite both CD4+ and CD8+ T cell subsets expressing granzymes, pore-forming protein, TNF-beta, and TNF-alpha, these T cell subsets displayed distinct pathways of antibody-redirected lysis against TNF-sensitive and TNF-resistant targets, even in the presence of anti-TNF antibodies. In addition, these same effector T cell subsets were also directly cytotoxic (in the absence of heteroconjugated antibody) against TNF-sensitive targets in an 18-h assay. Indeed, this direct cytotoxicity was completely abrogated by anti-TNF-alpha antibody and was sensitive to the metabolic inhibitors (cyclosporin A, CT, cycloheximide, and actinomycin D), all of which blocked CD4+/CD8+ T cell TNF-alpha production. Therefore, both CD4+ and CD8+ T cells were demonstrated to utilize antibody and lymphokine-mediated lytic mechanisms. CD4+ and CD8+ effector subsets were demonstrated to lyse the same TNF-sensitive target by these two different mechanisms. Although it cannot be excluded that the redirected lytic mechanisms of both CD4+ and CD8+ effectors share common elements, it is likely that other important events in this cytolytic process are fundamentally distinct between these subsets of T cells.

Published
1992
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5. IL-8 gene expression and production in human peripheral blood lymphocyte subsets

Author

Mark Smyth, Zachariae, C. O. C., Norihisa, Y., Ortaldo, J. R., Hishinuma, A., and Matsushima, K.

Subjects
Immunology, Immunology and Allergy
Abstract

We have investigated IL-8 mRNA expression and IL-8 production in highly purified subsets of peripheral blood lymphocytes. T cells stimulated with PHA, ionomycin, or PMA alone failed to express IL-8 mRNA. However T cells stimulated with a combination of PMA and ionomycin or PMA and PHA expressed IL-8 mRNA in a PMA dose-dependent manner and maximally after 3 to 6 h of culture. Induction of IL-8 mRNA appeared to be specifically in the CD4+ T cell subset. Surprisingly, however, T cells were not induced to secrete significant levels of IL-8 polypeptide, even in the presence of accessory monocytes. In addition, immunoprecipitation analysis of PMA/ionomycin-treated T cell lysates detected only minor levels of cellular IL-8 Ag thereby suggesting that in T cells, the production of IL-8 was inhibited at the posttranscriptional level. By contrast, CD3- large granular lymphocytes (LGL) were both induced to express IL-8 mRNA and secrete biologically active IL-8 upon specific stimulation with IL-2 and ligand (anti-CD16 mAb) for the NK cell receptor for IgG-Fc (CD16), or upon nonspecific stimulation with PMA. IL-2 and anti-CD16 mAb synergistically induced IL-8 expression in LGL. Other nonactivating LGL-specific mAb did not induce LGL IL-8 secretion. The amount of IL-8 produced by activated LGL was donor variable, but generally 5 to 10 times less than that secreted by monocytes. The ability of LGL to release IL-8 and a large number of other cytokines further supports the hypothesis that LGL may contribute to both inflammatory and immunologic responses.

Published
1991
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6. IL-2 and IL-6 synergize to augment the pore-forming protein gene expression and cytotoxic potential of human peripheral blood T cells

Author

Smyth, M. J., Ortaldo, J. R., Bere, W., Yagita, H., Okumura, K., and Howard Young

Subjects
Immunology, Immunology and Allergy
Abstract

Our previous studies have demonstrated that high dose IL-2 (1000 U/ml) alone can induce human peripheral blood T cell pore-forming protein (PFP) mRNA expression and cytotoxic potential. We now report that the levels of IL-2 needed to induce these effects in T cells can be significantly reduced in the presence of IL-6. IL-6 and suboptimal doses of IL-2 (10 U/ml) were found to costimulate PFP mRNA expression and cytotoxic potential in resting human peripheral blood T cells, whereas IL-6 or low dose IL-2 alone had no effect. The induction of T cell PFP mRNA by IL-2/IL-6 was extremely rapid and increases in both PFP mRNA expression and cytotoxic potential were IL-6 dose dependent. The costimulatory effect of IL-6 did not appear to involve the IL-2/IL-2R pathway in as much as IL-6 did not induce IL-2 production or detectably increase IL-2R surface expression in T cells. These findings, in addition to the rapid induction of PFP mRNA by IL-2/IL-6, suggested that IL-6 can directly and independently provide an additional signal to augment the differentiation of CTL. In contrast to the results observed in T cells, IL-6 and IL-2 could enhance CD3- large granular lymphocyte (LGL) NK activity, but IL-6 either alone or in combination with IL-2 had no effect on constitutive PFP mRNA expression in resting LGL. These data further confirm that different mechanisms may be responsible for lymphokine activation of CTL and LGL in human peripheral blood. In particular it appears that IL-6 acts as a costimulatory signal with IL-2 in generating CTL and that IL-6 functions in part by acting in synergy with IL-2 to induce PFP, a major lytic protein involved in lymphocyte cytotoxicity.

Published
1990
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18. Regulation of JAK3 expression and activation in human B cells and B cell malignancies.

Author

Tortolani, P J, primary, Lal, B K, additional, Riva, A, additional, Johnston, J A, additional, Chen, Y Q, additional, Reaman, G H, additional, Beckwith, M, additional, Longo, D, additional, Ortaldo, J R, additional, Bhatia, K, additional, McGrath, I, additional, Kehrl, J, additional, Tuscano, J, additional, McVicar, D W, additional, and O'Shea, J J, additional

Published
1995
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