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

Srinivas Nagaraj, Kapil Gupta, Vladimir Pisarev, Leo Kinarsky, Simon Sherman, Loveleen Kang, Donna L. Herber, Jonathan Schneck, Dmitry I. Gabrilovich

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612 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)828-835
Number of pages8
JournalNature Medicine
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2007

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nagaraj, S., Gupta, K., Pisarev, V., Kinarsky, L., Sherman, S., Kang, L., Herber, D. L., Schneck, J., & Gabrilovich, D. I. (2007). Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nature Medicine, 13(7), 828-835. https://doi.org/10.1038/nm1609