Peripheral deletion of autoreactive CD8 T cells by cross presentation of self-antigen occurs by a Bcl-2-inhibitable pathway mediated by Bim.
By transgenic expression of ovalbumin (OVA) as a model self antigen in the beta cells of the pancreas, we have shown that self tolerance can be maintained by the cross-presentation of this antigen on dendritic cells in the draining lymph nodes. Such cross-presentation causes initial activation of OVA-specific CD8 T cells, which proliferate but are ultimately deleted; a process referred to as cross-tolerance. Here, we investigated the molecular basis of cross-tolerance. Deletion of CD8 T cells was prevented by overexpression of Bcl-2, indicating that cross-tolerance was mediated by a Bcl-2 inhibitable pathway. Recently, Bim, a pro-apoptotic Bcl-2 family member whose function can be inhibited by Bcl-2, was found to play a critical role in the deletion of autoreactive thymocytes, leading us to examine its role in cross-tolerance. Bim-deficient T cells were not deleted in response to cross-presented self-antigen, strongly implicating Bim as the pro-apoptotic mediator of cross-tolerance.
Davey
Gayle M
GM
The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.
Kurts
Christian
C
Miller
Jacques F A P
JF
Bouillet
Philippe
P
Strasser
Andreas
A
Brooks
Andrew G
AG
Carbone
Francis R
FR
Heath
William R
WR
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D007328:Insulin / Q000235:genetics; D008212:Lymphocyte Depletion / Q000379:methods*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D007328:Insulin; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D010047:Ovalbumin