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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901676v1 183/10/6114    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Gurung, P. Articles by Griffith, T. S. PubMed PubMed Citation Articles by Gurung, P. Articles by Griffith, T. S.

Activation-Induced CD154 Expression Abrogates Tolerance Induced by Apoptotic Cells¹

Prajwal Gurung,^* Tamara A. Kucaba,^* Thomas A. Ferguson, and Thomas S. Griffith^2*

^*Department of Urology and Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; and Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110

The decision to generate a productive immune response or tolerance often depends on the context in which T cells first see Ag. Using a classical system of tolerance induction, we examined the immunological consequence of Ag encountered in the presence of naive or activated apoptotic cells. Naive apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154, as tolerance resulted after i.v. injection of either naive or activated apoptotic CD154^–/– T cells, while coinjection of an agonistic anti-CD40 mAb with naive apoptotic T cells induced robust immunity. Dendritic cells fed activated apoptotic T cells in vitro produced IL-12p40 in a CD154-dependent manner, and the use of IL-12p40^–/– mice or mAb-mediated neutralization of IL-12 revealed a link between CD154, IL-12, and the ability of activated apoptotic T cells to induce immunity rather than tolerance. Collectively, these results show that CD154 expression on apoptotic T cells can determine the outcome of an immune response to Ag recognized within the context of the apoptotic cells and suggest that the balance between naive and activated apoptotic T cells may dictate whether a productive immune response is encouraged.

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 and R56 AI077565 (to T.S.G.).

² Address correspondence and reprint requests to Dr. Thomas S. Griffith, Department of Urology, 3204 MERF, University of Iowa, 375 Newton Road, Iowa City, IA 52242-1089. E-mail address: thomas-griffith{at}uiowa.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; TNP, trinitrophenyl; DC, dendritic cell; DAMP, damage-associated molecular pattern; iNOS, inducible NO synthase; TNBS, 2,4,6-trinitrobenzene sulfonic acid.

⁴ The online version of this article contains supplemental material.