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An Essential Role for TNF in Modulating Thresholds for Survival, Activation, and Tolerance of CD8⁺ T Cells¹

Ioannis Chatzidakis^*,, Georgia Fousteri^*,, Debbie Tsoukatou^*, George Kollias and Clio Mamalaki^2,*

^* Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Vassilika Vouton, Crete, Greece; Department of Biology, University of Crete, Crete, Greece; and Biomedical Sciences Research Center Alexander Fleming, Vari, Greece

TNF and its receptors p55 and p75 are known to be important in the homeostasis of the peripheral immune system. Previous studies have presented apparently contradictory evidence for an in vivo role of TNF in T cells. In this study, we analyzed TNF-deficient mice crossed with the F5 TCR-transgenic animals. We show that endogenous TNF modulates several aspects of homeostasis of peripheral F5 CD8 T cells. We found that F5/TNF^–/–mice had reduced numbers of peripheral F5 T cells, F5/TNF^–/– CD8 T cells exhibited reduced survival potential, and furthermore that T cell-derived TNF is required for optimum recovery of naive CD8 T cells in lymphopenic hosts, suggesting its involvement in the survival of peripheral CD8 T cells. Both peptide activation and ensuing Ag-induced apoptosis are quantitatively reduced in TNF^–/– CD8 T cells. The latter observations can be related to decreased binding activities of NF-B and NF-ATp observed in Ag-stimulated F5/TNF^–/– T cells. Finally, in a CD8 T cell tolerance model, endogenous TNF was necessary for several parameters of CD8 T cell tolerance induction. Collectively, our results provide evidence that endogenous TNF modulates thresholds in several ligand-driven T cell responses.

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 in part by the Reinforcement Program of Human Research Manpower Program of the Hellenic Secretariat for Research and Technology.

² Address correspondence and reprint requests to Dr. Clio Mamalaki, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Vassilika Vouton, P.O. Box 1385 GR 711 10 Heraklion, Crete, Greece. E-mail address: mamalaki{at}imbb.forth.gr

³ Abbreviations used in this paper: TNFR, TNF receptor; PI, propidium iodide; AICD, activation-induced cell death; SNARF, carboxylic acid acetate succinimidyl ester.

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