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Original Article

^a Cellular Immunology Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892
^b Department of Pathology, George Washington University, Washington, DC 20037
Rm. 332, Bldg. 30, Cellular Immunology Section, OIIB, NIDCR, National Institutes of Health, Bethesda, MD 20892.301-402-1064301-496-4178

smwahl{at}dir.nidcr.nih.gov

Transforming growth factor (TGF)-β1, 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-β1 (TGF-β1^–/–) 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 receptor in peripheral T cells. Strikingly, TGF-β was localized within the mitochondria of normal T cells, and the absence of TGF-β1 resulted in disruption of mitochondrial membrane potential (_m), which marks the point of no return in a cell condemned to die. This TGF-β–dependent regulation of viability appears dissociable from the TGF-β1 membrane receptor–Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl–XL. Thus, TGF-β1 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.

Key Words: TCR • mitochondrial membrane potential • Fas/TNF- receptor • Smad3 • Bcl–XL

Abbreviations used in this paper: 7-AAD, 7-amino-actinomycin D; _m, mitochondrial membrane potential; AICD, activation-induced cell death; DiOC₆, 3,3'-dihexyloxacarbocyanine iodide; DP, double positive; ER, endoplasmic reticulum; FasL, Fas ligand; GAPDH, glyceraldehyde 3-phosphate dehydrogenase gene; PALS, periarteriolar lymphatic sheath; TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling.

© 2001 The Rockefeller University Press

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This article has been cited by other articles:

• Golstein, P., Wyllie, A. H. (2001). T Cell Death and Transforming Growth Factor {beta}1. JEM 194: f19-f22 [Full Text]  

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