Submitted October 22, 2008
Accepted February 1, 2009
The molecular signature of CD8+ T cells undergoing deletional tolerance
Ian A. Parish*, Sudha Rao, Gordon K. Smyth, Torsten Juelich, Gareth S. Denyer, Gayle M. Davey, Andreas Strasser, and William R. Heath
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Acton, Australian Capital Territory, Australia
School of Molecular and Microbial Biosciences, University of Sydney, Sydney, New South Wales, Australia
Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia
* Corresponding author; email: ian.parish{at}yale.edu.
Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T cell anergy or deletion. While the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T cell deletion. Here, we determined the gene expression signature of peripheral CD8+ T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the pro-apoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T cell deletion. Bim up-regulation was paralleled by defective IL-7R
chain re-expression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised.
