Activation with superantigens induces programmed death in antigen‐primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18‐dependent mechanism

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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 Vβ 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+]j) and transcription of a number of cytokine genes including interleukin‐2 (IL‐2), IL‐4, interferon‐γ (IFN‐γ), 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‐1a, IL‐2, IL‐4, IL‐6, GM‐CSF, IFN‐γ, tumor necrosis factor (TNF‐α, or TNF‐β), 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/Tcell 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‐γ. 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.