Requirement for transforming growth factor beta 1 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 t hymic and peripheral T cell apoptosis was increased in mice lacking TGF-bet a1 (TGF-beta1(-/-)) compared with wild-type littermates. Engagement of the T cell receptor enhanced this aberrant T cell apoptosis, as did signaling t hrough either the death receptor Fas or the tumor necrosis factor alpha rec eptor in peripheral T cells. Strikingly, TGF-beta was localized within the mitochondria of normal T cells, and the absence of TGF-beta1 resulted in di sruption of mitochondrial membrane potential (Delta Psi (m)), which marks t he point of no return in a cell condemned to die. This TGF-beta -dependent regulation of viability appears dissociable from the TGF-beta1 membrane rec eptor-Smad3 signaling pathway, but associated with a mitochondrial antiapop totic 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 toler ance, but also for defining the mechanisms of programmed cell death in gene ral.