The Bcl-2 family pro-apoptotic molecule, BNIP3 regulates activation-induced cell death of effector cytotoxic T lymphocytes.
BNIP3 is a recently described pro-apoptotic member of the Bcl-2 family and in BNIP3 cDNA-transfected cell lines, cell death occurs via a caspase-independent pathway with opening of the mitochondrial permeability transition (PT) pore and rapid loss of mitochondrial transmembrane potential (Delta psi m). However, its expression or function in physiologic cell types is not known. Our results using the T-cell receptor transgenic mice P14, specific for lymphocyte choreomeningitis virus (LCMV) glycoprotein, show that in contrast to the other Bcl-2 family pro-apoptotic molecules, BNIP3 is transcriptionally highly up-regulated in effector cytotoxic T lymphocytes (CTL). Because CTL have a propensity to undergo activation-induced cell death (AICD) upon restimulation, we tested for other features associated with BNIP3-induced cell death. AICD of CTL was caspase-independent as determined by measuring caspase activation during target cell killing as well as by lack of inhibition with caspase inhibitors. Moreover, similar to BNIP3-induced cell death, CTL apoptosis was associated with increased production of reactive oxygen species and decreased Delta psi m. Finally, retroviral transduction of BNIP3 antisense RNA diminished AICD in effector CTL. These results suggest that BNIP3 may play an important role in T-cell homeostasis by regulating effector CTL numbers.
Wan
J
J
The Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA. swany@cbr.med.harvard.edu
Martinvalet
D
D
Ji
X
X
Lois
C
C
Kaech
S M
SM
Von Andrian
U H
UH
Lieberman
J
J
Ahmed
R
R
Manjunath
N
N
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D008213:Lymphocyte Activation / Q000276:immunology*; D008564:Membrane Potentials / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000276:immunology
D000590:Amino Acid Chloromethyl Ketones; C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; D061945:Caspase Inhibitors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases