Induction of abortive and productive proliferation in resting human T lymphocytes via CD3 and CD28.

How the T-cell receptor (TCR)/CD3 complex mediates positive as well as negative signals for T-cell regulation is not fully understood. We have previously described the induction of anergy in resting human T lymphocytes after mitogenic, high-dose CD3 triggering with monoclonal antibodies. Here we report the concomitantly occurring cell death to be largely caused by apoptosis, which mainly affects the CD4+ T-helper population. Because cell death becomes detectable after initial cell proliferation, it appears that a high-dose CD3 stimulus constitutes a negative signal for resting T cells leading to an 'abortive proliferation' that is followed by anergy and/or apoptosis of the cells. In contrast, if initial proliferation is induced by a low dose of anti-CD3 in the presence of an accessory signal via the CD28 receptor, anergy and cell death are markedly reduced and 'productive proliferation' may occur. Productive proliferation is characterized by an increased secretion of various cytokines measured (interleukin (IL)-2, IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma)). A low-dose submitogenic CD3 stimulus induced neither anergy nor cell death, supporting the view that negative CD3 signalling requires proliferation of resting cells.