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Dynamic Control of Self-Specific CD8⁺ T Cell Responses via a Combination of Signals Mediated by Dendritic Cells¹

Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol, United Kingdom

It is acknowledged that T cell interactions with mature dendritic cells (DC) lead to immunity, whereas interactions with immature DC lead to tolerance induction. Using a transgenic murine system, we have examined how DC expressing self-peptides control naive, self-reactive CD8⁺ T cell responses in vitro and in vivo. We have shown, for the first time, that immature DC can also stimulate productive activation of naive self-specific CD8⁺ T cells, which results in extensive proliferation, the expression of a highly activated cell surface phenotype, and differentiation into autoimmune CTL. Conversely, mature DC can induce abortive activation of naive CD8⁺ T cells, which is characterized by low-level proliferation, the expression of a partially activated cell surface phenotype which does not result in autoimmune CTL. Critically, both CD8⁺ T cell responses are determined by a combination of signals mediated by the DC, and that altering any one of these signals dramatically shifts the balance between autoimmunity and self-tolerance induction. We hypothesize that DC maintain the steady state of self-tolerance among self-specific CD8⁺ T cells in an active and dynamic manner, licensing productive immune responses against self-tissues only when required.

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 Juvenile Diabetes Research Foundation Grant 1-2000-99 (to D.J.M.). B.J.E.R. was in receipt of Medical Research Council U.K. Studentship G78/7503.

² Address correspondence and reprint requests to Dr. David J. Morgan, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, U.K.

³ Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; mDC, mature DC; BM, bone marrow; HA, hemagglutinin; dd, double distilled; HPRT, hypoxanthine phosphoribosyltransferase; PLN, pancreatic lymph node.

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