IFN-gamma 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 signals.
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-Guérin (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 IFN-gamma-dependent up-regulation of many diverse apoptosis-pathway genes in effector CD4(+) T cells. Unexpectedly, IFN-gamma 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-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 TNFR1. 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, TNFR1, 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.
Li
Xujian
X
Trudeau Institute, Saranac Lake, NY 12983, USA.
McKinstry
K Kai
KK
Swain
Susan L
SL
Dalton
Dyana K
DK
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; D007371:Interferon-gamma; D020169:Caspases