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  • Title: Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18-dependent mechanism.
    Author: Damle NK, Leytze G, Klussman K, Ledbetter JA.
    Journal: Eur J Immunol; 1993 Jul; 23(7):1513-22. PubMed ID: 8100773.
    Abstract:
    Staphylococcal enterotoxin superantigens (SAg) bind class II major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC) and upon cell-to-cell contact stimulate proliferation of T cells expressing appropriate V beta gene products. In addition, SAg can also deliver negative signals to Ag-specific T cells resulting in a state of unresponsiveness or a loss of viability. The present study examines the functional consequences of a direct interaction of SAg with alloAg-specific class II MHC+ CD4+ T cell lines (TCL). Our results demonstrate that SAg induce programmed death (apoptosis) in a majority of Ag-specific CD4+ T cells accompanied by genomic DNA fragmentation. SAg binding to Ag-specific TCL resulted in a rapid mobilization of intracellular free calcium ([Ca2+]i) and transcription of a number of cytokine genes including interleukin-2(IL-2), IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granzyme B indicating the activation of primed T cells. Both SAg-induced cytokine gene expression as well as subsequent death were significantly inhibited by a tyrosine kinase inhibitor herbimycin A and also by cyclosporin A. SAg-induced death of primed T cells was also inhibited by monoclonal antibodies (mAb) directed at the CD11a/CD18 molecule but not those reactive with other T cell surface molecules such as CD2, CD7, CD28, CD29 or CD49d. None of these mAb, including anti-CD11a/CD18, had any effect on SAg-induced expression of IL-2 and IL-4 genes or SAg-induced [Ca2+]i response. Addition of cytokines such as IL-1 alpha, IL-2, IL-4, IL-6, GM-CSF, IFN-gamma, tumor necrosis factor (TNF-alpha, or TNF-beta), or neutralizing Ab to these cytokines had no effect on SAg-induced death of Ag-specific TCL. The T cells which survived the death-inducing effects of SAg showed down-regulation of the CD3/T cell receptor and up-regulation of CD2 and HLA-DR expression, and upon re-exposure to the same SAg upregulated expression of mRNA for IL-2 and IFN-gamma. Presentation of SAg by B7+ ICAM-1+ LFA-3+ DR+ professional APC was also able to induce the death of Ag-specific TCL. Together these results suggest that the activation with SAg causes programmed death of Ag-specific TCL cells via a mechanism that requires late participation of the CD11a/CD18 molecule.
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