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Nat Med. 2007 Jul;13(7):828-35. Epub 2007 Jul 1.

Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer.

Author information

1
H. Lee Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, Florida 33647, USA.

Abstract

Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide-major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC. These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.

PMID:
17603493
PMCID:
PMC2135607
DOI:
10.1038/nm1609
[Indexed for MEDLINE]
Free PMC Article

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