International Immunology, Vol. 11, No. 8, 1225-1238,
August 1999
© 1999 Japanese Society for Immunology
Death by neglect as a deletional mechanism of peripheral tolerance
Ecole Normale Supérieure de Lyon, INSERM U98, 46 Allée d'Italie, 69364 Lyon Cedex 07, France
1 Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, NSW 2042, Australia
Correspondence to: P. Bertolino
In contrast to most organs, the anatomy of the liver may allow naive CD8+ T cells to make direct contact with liver parenchymal cells. We have previously shown, using a combination of TCR transgenic T cells specific for H-2 Kb and hepatocytes expressing a transgenic H-2 Kb molecule, that hepatocytes can induce antigen-specific activation and proliferation of naive CD8+ T cells independently of CD28 co-stimulation. However, T cell activation by hepatocytes leads to premature T cell death and tolerance, bothin vivo andin vitro. In this study, we investigated the mechanisms of T cell death induced by hepatocytesin vitro using primary hepatocytes to activate purified CD8+ T cells. Neither Fas nor tumor necrosis factor receptor were involved, indicating that hepatocyte- induced death was distinct from activation-induced cell death. Before they started to divide, T cells activated by hepatocytes expressed lower levels of thebcl-xL survival gene and 30 times less IL-2 mRNA than CD8+ cells activated by splenic antigen-presenting cells. Since CD28 co-stimulation increases both IL-2 andbcl-xL expression, this suggests that hepatocyte-activated T cells die by neglect because they fail to receive effective co-stimulatory signals. In agreement with this model, premature death promoted by hepatocytes could be prevented by cross-linking CD28. Survival after CD28 cross-linking correlated with increased IL-2 andbcl-xL expression, and sustained T cell proliferation, while cytotoxic T lymphocyte activity was prolonged as compared with cells stimulated without CD28 co-stimulation. This study confirms that high- affinity TCR transgenic antigen-specific CD8+ T cells can be activated to proliferate and differentiate into cytotoxic effector cells. However, prolonged T cell survival and cytotoxicity required CD28 co-stimulation as well. To our knowledge, this is the first report suggesting that tolerance in the context of lack of CD28 co-stimulation can result from Fas-independent peripheral deletion rather than from anergy.
Keywords: activation-induced cell death, co-stimulation, hepatocytes, T lymphocytes, tolerance
Transmitting editor: D. Tarlinton
2 Present address: Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, NSW 2042, Australia
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