The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen.
The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet beta-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim-/- clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.
Redmond
William L
WL
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Wei
Cheng-Hong
CH
Kreuwel
Huub T C
HT
Sherman
Linda A
LA
D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017637:Clonal Deletion; D000068876:Fingolimod Hydrochloride; D005947:Glucose / Q000032:analysis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011409:Propylene Glycols / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D017634:Self Tolerance; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; C491899:Fas protein, mouse; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D019014:fas Receptor; D000068876:Fingolimod Hydrochloride; D005947:Glucose; D013110:Sphingosine