The Journal of Experimental Medicine
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Published online 14 October 2002 doi:10.1084/jem.20020861
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© Rockefeller University Press, 0022-1007/2002/10/1099 $5.00
The Journal of Experimental Medicine, Volume 196, Number 8, 1099-1104

Brief Definitive Report

The CD8{alpha}+ Dendritic Cell Is Responsible for Inducing Peripheral Self-Tolerance to Tissue-associated Antigens

Gabrielle T. Belz1, Georg M.N. Behrens1, Chris M. Smith1, Jacques F.A.P. Miller1, Claerwen Jones2, Kristina Lejon3, C. Garrison Fathman3, Scott N. Mueller2, Ken Shortman1, Francis R. Carbone2 and William R. Heath1

1 Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia
2 Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia
3 Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305

Address correspondence to William R. Heath or Gabrielle T. Belz, Immunology Division, The Walter and Eliza Hall Institute, P.O. Royal Melbourne Hospital, Parkville 3050, Victoria, Australia. Phone: 61-03-9345-2482; Fax: 61-3-9347-0852; E-mail: heath{at}wehi.edu.au or belz{at}wehi.edu.au

We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow–derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8{alpha}+ dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced ß-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c+CD8{alpha}+ cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8{alpha}+ DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.

Key Words: antigen presentation • cross-tolerance • CD8+ T cells • dendritic cells • cross-presentation


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