T Cell Death and Transforming Growth Factor β1

The TGF-␤ family comprises many cytokines involved in the control of cell fate (1). Some of these have been shown to control cell death. For instance, at least one of the members of the BMP subfamily of the TGF-␤ family is required in interdigital death, a classical model of developmentally programmed cell death (2). Another TGF-␤ family member, TGF-␤ 1, entertains a complicated relationship with cell death, of lymphocytes in particular. When added extracellularly, it has been reported to induce death of B lymphocytes (3, 4) and to prevent T lymphocyte death (5–7). A new, and at times somewhat heretical twist, is now reported (8). In mice homozygous for a TGF-␤ 1 null mutation (9, 10), thus not expressing TGF-␤ 1, W.J. Chen et al. (8) found that apparently spontaneous apoptosis of both thymic and peripheral T cells was increased compared with wild-type controls. These findings might seem relatively trivial, since TGF-␤ 1 had previously been shown to prevent T cell death (see above). However, not only was spontaneous T cell death impressive in both thymus and peripheral organs, but results were even more striking when T cells were challenged with anti-CD3 antibody (mimicking stimulation through the TCR). In vitro experiments already showed an increased sensitivity of T cells from TGF-␤ 1 knockout mice, resulting in marked activation induced cell death. The most spectacular results were obtained with in vivo injection of anti-CD3 antibody into TGF-␤ 1 knockout mice, leading to massive apoptosis in both thymus and spleen, visible as terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells within hours, and effecting considerable reduction in lymphoid organ cell numbers. This was accompanied by an increase in expression of Fas and Fas ligand in spleen cells, and increase in sensitivity to the Fas pathway and in some situations to the TNFR2 pathway of cell death. These results demonstrated that activated lymphocytes in vivo require TGF-␤ 1 to protect them from death. More surprising results followed (8). TGF-␤ 1, and more generally all members of the TGF-␤ family, are known to affect cells from the outside through cognate cell surface receptors , the engagement of which lead to intracellular activation of Smad transcription factors, especially Smad3 in the case of TGF-␤ 1 (1, 11, 12). However, the current work (8) suggests that the protective effects of TGF-␤ 1 might be due to intracellular TGF-␤ 1. Two lines of evidence support this. …