Journal
JOURNAL OF IMMUNOLOGY
Volume 179, Issue 2, Pages 939-949Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.2.939
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Funding
- AHRQ HHS [HS63925] Funding Source: Medline
- NHLBI NIH HHS [P01 HL063925] Funding Source: Medline
- NIAID NIH HHS [P01 AI046530, P01 AI045666, AI45666, AI46530] Funding Source: Medline
- NINDS NIH HHS [R01 NS043355-04, R01 NS043355-03, R01 NS043355-01A1, R01 NS043355-02, R01 NS043355-05, NS 043355, R01 NS043355] Funding Source: Medline
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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-gamma in regulating apoptosis of CD4(+) T cells during bacillus Calmette-Guerin (BCG) infection of mice. Our data provide new insight into the regulation of CD4(+) T cell apoptosis by IFN-gamma. As CD4(+) T cells responded to BCG infection, there was a coordinated increase in IFN-gamma production by effector CD4(+) T cells and a coordinated transcripts and protein expression of Bel-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-gamma knockout, CD4(+) T cells underwent apoptosis that was associated with damaged mitochondrial membranes. IFN-gamma also up-regulated expression of cell-extrinsic signals of apoptosis, including TRAIL, DR5, and TNFRL Cell-extrinsic apoptosis signals from TNF-alpha, TRAIL, and NO were capable of damaging the mitochondrial membranes in activated CD4(+) T cells. Moreover, activated CD4(+) T cells from BCG-infected DR5, TNFRL and inducible NO synthase knockout mice had impaired caspase-9 activity, suggesting impaired mitochondria-pathway apoptosis. We propose that IFN-gamma 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.
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