Article abstract

Nature Medicine 13, 828 - 835 (2007)
Published online: 1 July 2007 | doi:10.1038/nm1609

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

Srinivas Nagaraj1, Kapil Gupta2, Vladimir Pisarev3, Leo Kinarsky3, Simon Sherman3, Loveleen Kang1, Donna L Herber1, Jonathan Schneck2 & Dmitry I Gabrilovich1

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.

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  1. H. Lee Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, Florida 33647, USA.
  2. John Hopkins University Medical School, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
  3. University of Nebraska Medical Center and Eppley Cancer Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198, USA.

Correspondence to: Dmitry I Gabrilovich1 e-mail: dmitry.gabrilovich@moffitt.org



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