Requirement for transforming growth factor beta1 in controlling T cell apoptosis.
Transforming growth factor (TGF)-beta1, a potent immunoregulatory molecule, was found to control the life and death decisions of T lymphocytes. Both thymic and peripheral T cell apoptosis was increased in mice lacking TGF-beta1 (TGF-beta1(-/-)) compared with wild-type littermates. Engagement of the T cell receptor enhanced this aberrant T cell apoptosis, as did signaling through either the death receptor Fas or the tumor necrosis factor alpha receptor in peripheral T cells. Strikingly, TGF-beta was localized within the mitochondria of normal T cells, and the absence of TGF-beta1 resulted in disruption of mitochondrial membrane potential (Deltapsi(m)), which marks the point of no return in a cell condemned to die. This TGF-beta-dependent regulation of viability appears dissociable from the TGF-beta1 membrane receptor-Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl-XL. Thus, TGF-beta1 may protect T cells at multiple sites in the death pathway, particularly by maintaining the essential integrity of mitochondria. These findings may have broad implications not only for T cell selection and death in immune responses and in the generation of tolerance, but also for defining the mechanisms of programmed cell death in general.
Chen
W
W
Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jin
W
W
Tian
H
H
Sicurello
P
P
Frank
M
M
Orenstein
J M
JM
Wahl
S M
SM
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008854:Microscopy, Electron; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology
D015703:Antigens, CD; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D016212:Transforming Growth Factor beta; D019014:fas Receptor