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IFN- Acts Directly on Activated CD4⁺ T Cells during Mycobacterial Infection to Promote Apoptosis by Inducing Components of the Intracellular Apoptosis Machinery and by Inducing Extracellular Proapoptotic Signals¹

Trudeau Institute, Saranac Lake, NY 12983

Despite many studies, the regulation of CD4⁺ T cell apoptosis during the shutdown of immune responses is not fully understood. We have investigated the molecular mechanisms of IFN- in regulating apoptosis of CD4⁺ T cells during bacillus Calmette-Guérin (BCG) infection of mice. Our data provide new insight into the regulation of CD4⁺ T cell apoptosis by IFN-. As CD4⁺ T cells responded to BCG infection, there was a coordinated increase in IFN- production by effector CD4⁺ T cells and a coordinated IFN--dependent up-regulation of many diverse apoptosis-pathway genes in effector CD4⁺ T cells. Unexpectedly, IFN- up-regulated transcripts and protein expression of Bcl-2, Bax, Bim, Bid, Apaf-1, and caspase-9 in activated CD4⁺ T cells—components of the apoptosis machinery that are involved in promoting mitochondrial damage-mediated apoptosis. Wild-type, but not IFN- knockout, CD4⁺ T cells underwent apoptosis that was associated with damaged mitochondrial membranes. IFN- also up-regulated expression of cell-extrinsic signals of apoptosis, including TRAIL, DR5, and TNFR1. Cell-extrinsic apoptosis signals from TNF-, TRAIL, and NO were capable of damaging the mitochondrial membranes in activated CD4⁺ T cells. Moreover, activated CD4⁺ T cells from BCG-infected DR5, TNFR1, and inducible NO synthase knockout mice had impaired caspase-9 activity, suggesting impaired mitochondria-pathway apoptosis. We propose that IFN- promotes apoptosis of CD4⁺ T cells during BCG infection as follows: 1) by sensitizing CD4⁺ T cells to apoptosis by inducing intracellular apoptosis molecules and 2) by inducing cell-extrinsic apoptosis signals that kill CD4⁺ effector T cells.

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 grants (to D.K.D.) from the National Institutes of Health (Grant NS 043355) and from the National Multiple Sclerosis Society (Grant RG 3820A2/01). S.L.S. and K.K.M. were supported by National Institutes of Health Grants AI45666, AI46530, and HL63925.

² Address correspondence and reprint requests to Dr. Dyana K. Dalton, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: ddalton{at}trudeauinstitute.org

³ Abbreviations used in this paper: KO, knockout; BCG, bacillus Calmette-Guérin; iNOS, inducible NO synthase; WT, wild type; DR5, death receptor 5; ROS, reactive oxygen species; 7-AAD, 7-aminoactinomycin D; TCM, T cell medium; MnTBAP, manganese (III) tetrakis 4-benzoic acid; SNAP, S-nitroso-N-acetyl-penicillamine; _m, mitochondrial transmembrane potential.

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