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* Department of Urology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242;
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110; and
Department of Immunology, St. Jude Children’s Hospital, Memphis, TN 38105
The decision to generate a productive immune response or immune tolerance following pathogenic insult often depends on the context in which T cells first encounter Ag. The presence of apoptotic cells favors the induction of tolerance, whereas immune responses generated with necrotic cells promote immunity. We have examined the tolerance induced by injection of apoptotic cells, a system in which cross-presentation of Ag associated with the dead cells induces CD8+ regulatory (or suppressor) T cells. We observed that haptenated apoptotic cells induced CD8+ suppressor T cells without priming CD4+ T cells for immunity. These CD8+ T cells transferred unresponsiveness to naive recipients. In contrast, haptenated necrotic cells stimulated immunity, but induced CD8+ suppressor T cells when CD4+ T cells were absent. We further found that CD8+ T cells induced by these treatments displayed a "helpless CTL" phenotype and suppress the immune response by producing TRAIL. Animals deficient in TRAIL were resistant to tolerance induction by apoptotic cells. Thus, the outcome of an immune response taking place in the presence of cell death can be determined by the presence of CD4+-mediated Th cell function.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants CA109446 (to T.S.G.), EY06765 (to T.A.F.), EY015570 (to T.A.F.), and AI44848 (to D.R.G.), and the Department of Ophthalmology and Visual Sciences Core Grant (EY08972). Support was also received from the Foundation for Fighting Blindness (Owings Mills, MD) and from Research to Prevent Blindness (New York, NY).
2 Address correspondence and reprint requests to Dr. Thomas A. Ferguson, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid, Box 8096, St. Louis, MO 63110. E-mail address: Ferguson{at}vision.wustl.edu
3 Abbreviations used in this paper: DC, dendritic cell; Ts, T suppressor cell; Treg, regulatory T cell; TNBS, 2,4,6 trinitrobenzene sulfonic acid; TNP, trinitrophenyl; TNP-spl, TNP-coupled spleen; AICD, activation-induced cell death.
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