The Journal of Experimental Medicine
VeriKine-HS Human Interferon-Beta Serum
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Published online 20 August 2001. doi:10.1084/jem.194.4.439
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© The Rockefeller University Press, 0022-1007/2001/8/439/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 4, August 20, 2001 439-454

Original Article

Requirement for Transforming Growth Factor β1 in Controlling T Cell Apoptosis

WanJun Chena, Wenwen Jina, Hongsheng Tiana, Paula Sicurellob, Mark Franka, Jan M. Orensteinb, and Sharon M. Wahla

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 {alpha} 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 ({Delta}{psi}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-{alpha} receptor • Smad3 • Bcl–XL

Abbreviations used in this paper: 7-AAD, 7-amino-actinomycin D; {Delta}{psi}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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