Transforming growth factor‐β promotes ‘death by neglect’ in post‐activated human T cells

Abstract

Summary: Transforming growth factor‐β (TGF‐β) is central to the wound repair processes that follow local trauma and inflammation. In order to mimic the early events of wound‐healing, we studied the effects of TGF‐β on mitogen‐stimulated peripheral blood cells. TGF‐β added at the initiation of mitogenesis did not significantly alter T‐cell activation, proliferation, CD45 isoform switching, or activation‐induced cell death. By contrast, TGF‐β added 72 hr post‐activation (or later) enhanced the cumulative increase in apoptotic T cells. TGF‐β had no effect on mitogen‐induced up‐regulation of Fas (CD95) or Fas ligand and did not enhance killing of the Fas‐sensitive Jurkat cell line by activated T cells. Furthermore, TGF‐β had no direct effect on levels of mRNA for members of the bcl family (bcl‐X, bfl‐1, bik, bak, bax, bcl‐2 and mcl‐1). These findings suggest that TGF‐β does not directly induce apoptosis via the Fas system or by direct effects on bcl proteins. However, interleukin‐2, which can ‘rescue’ lymphocytes from spontaneous apoptosis due to cytokine deprivation, abolished the pro‐apoptotic effects of TGF‐β on post‐activated T cells, thus demonstrating that TGF‐β increases the cytokine‐dependence of T cells for survival. We propose a novel role for TGF‐β in the suppression of inflammation by promoting the elimination of post‐activated T cells once the initiating stimulus has been resolved.