Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer
Top Cited Papers
- 1 July 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 13 (7), 828-835
- https://doi.org/10.1038/nm1609
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.Keywords
This publication has 43 references indexed in Scilit:
- Crystal structure of nitrated human manganese superoxide dismutase: Mechanism of inactivationFree Radical Biology & Medicine, 2006
- Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing HostCancer Research, 2006
- Mechanisms and functional significance of tumour-induced dendritic-cell defectsNature Reviews Immunology, 2004
- Peroxynitrite reactivity with amino acids and proteinsAmino Acids, 2003
- Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivityBlood, 2003
- An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53Gene Therapy, 2002
- Selective Nitration of Histone Tyrosine Residues in Vivo in Mutatect TumorsOnline Journal of Public Health Informatics, 2002
- Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivoBritish Journal of Clinical Pharmacology, 2002
- The formation of peroxynitrite in vivo from nitric oxide and superoxideChemico-Biological Interactions, 1995
- Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic miceNature, 1988