Death by neglect as a deletional mechanism of peripheral tolerance.
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 K(b) and hepatocytes expressing a transgenic H-2 K(b) 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, both in vivo and in vitro. In this study, we investigated the mechanisms of T cell death induced by hepatocytes in 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 the bcl-x(L) 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 and bcl-x(L) 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 and bcl-x(L) 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.
Ecole Normale Supérieure de Lyon, INSERM U98, 46 Allée d'Italie, 69364 Lyon Cedex 07, France.
P
P
Bertolino
M C
MC
Trescol-Biémont
J
J
Thomas
B
B
Fazekas de St Groth
M
M
Pihlgren
J
J
Marvel
C
C
Rabourdin-Combe
D000818:Animals; D017209:Apoptosis; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D017637:Clonal Deletion; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D017634:Self Tolerance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D016207:Cytokines; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051020:bcl-X Protein