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

Research output: Contribution to journalArticle

596 Citations (Scopus)

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

Fingerprint

T-cells
Nitration
T-Cell Antigen Receptor
Major Histocompatibility Complex
T-Lymphocytes
Antigens
Peptides
Neoplasms
Tumor Escape
CD8 Antigens
Peroxynitrous Acid
Molecular modeling
Dimers
Tyrosine
Tumors
Reactive Oxygen Species
Myeloid-Derived Suppressor Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nagaraj, S., Gupta, K., Pisarev, V., Kinarsky, L., Sherman, S., Kang, L., ... 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

Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. / Nagaraj, Srinivas; Gupta, Kapil; Pisarev, Vladimir; Kinarsky, Leo; Sherman, Simon; Kang, Loveleen; Herber, Donna L.; Schneck, Jonathan; Gabrilovich, Dmitry I.

In: Nature Medicine, Vol. 13, No. 7, 01.07.2007, p. 828-835.

Research output: Contribution to journalArticle

Nagaraj, S, Gupta, K, Pisarev, V, Kinarsky, L, Sherman, S, Kang, L, Herber, DL, Schneck, J & Gabrilovich, DI 2007, 'Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer', Nature Medicine, vol. 13, no. 7, pp. 828-835. https://doi.org/10.1038/nm1609
Nagaraj, Srinivas ; Gupta, Kapil ; Pisarev, Vladimir ; Kinarsky, Leo ; Sherman, Simon ; Kang, Loveleen ; Herber, Donna L. ; Schneck, Jonathan ; Gabrilovich, Dmitry I. / Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. In: Nature Medicine. 2007 ; Vol. 13, No. 7. pp. 828-835.
@article{eedb384fa0f64a41a104688f4323f98f,
title = "Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer",
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.",
author = "Srinivas Nagaraj and Kapil Gupta and Vladimir Pisarev and Leo Kinarsky and Simon Sherman and Loveleen Kang and Herber, {Donna L.} and Jonathan Schneck and Gabrilovich, {Dmitry I.}",
year = "2007",
month = "7",
day = "1",
doi = "10.1038/nm1609",
language = "English (US)",
volume = "13",
pages = "828--835",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer

AU - Nagaraj, Srinivas

AU - Gupta, Kapil

AU - Pisarev, Vladimir

AU - Kinarsky, Leo

AU - Sherman, Simon

AU - Kang, Loveleen

AU - Herber, Donna L.

AU - Schneck, Jonathan

AU - Gabrilovich, Dmitry I.

PY - 2007/7/1

Y1 - 2007/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34447118098&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447118098&partnerID=8YFLogxK

U2 - 10.1038/nm1609

DO - 10.1038/nm1609

M3 - Article

VL - 13

SP - 828

EP - 835

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 7

ER -