The Journal of Experimental Medicine
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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 ß1 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

Correspondence to: Sharon M. Wahl, Rm. 332, Bldg. 30, Cellular Immunology Section, OIIB, NIDCR, National Institutes of Health, Bethesda, MD 20892. Tel:301-496-4178 Fax:301-402-1064 E-mail:smwahl{at}dir.nidcr.nih.gov.

Transforming growth factor (TGF)-ß1, 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-ß1 (TGF-ß1-/-) 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-ß was localized within the mitochondria of normal T cells, and the absence of TGF-ß1 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-ß–dependent regulation of viability appears dissociable from the TGF-ß1 membrane receptor–Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl–XL. Thus, TGF-ß1 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


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