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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.

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Figure 1: MSDCs disrupt binding of pMHC to CD8+ T cells.
Figure 2: Mechanism of MDSC-induced T-cell tolerance.
Figure 3: Effect of peroxynitrite donor on specific CD8+ T-cell activity.
Figure 4: Role of MDSCs in the nitration of tyrosine in CD8+ T cells.
Figure 5: Interaction between MDSCs and CD8+ T cells.
Figure 6: MDSCs induce CD8+ T-cell tolerance in tumor-bearing mice.

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Acknowledgements

We thank S. Kusmartsev for assistance at the beginning of this project and J. DeComarmond for technical assistance with manuscript preparation. This work was supported by the National Institutes of Health (grant RO1CA 84488 to D.I.G.) and, in part, by the Analytic Microscopy and Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center.

Author information

Authors and Affiliations

Authors

Contributions

S.N. performed most of the experiments, analyzed data and wrote the manuscript; K.G. performed some of binding experiments; V.P. contributed to overall research design and molecular modeling analysis; L.K. performed molecular modeling analysis; S.S. performed molecular modeling analysis; L.K. performed immunohistology in human tissues; D.H. performed immunohistology in mouse tissues; J.S. contributed to overall research design and analysis; D.I.G. designed the experiments, analyzed the data, wrote the manuscript and supervised the project.

Corresponding author

Correspondence to Dmitry I Gabrilovich.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Experimental model of MDSC-induced T-cell tolerance. (PDF 259 kb)

Supplementary Fig. 2

MSDC disrupt binding of pMHC to to CD8+ T cells in 2C models. (PDF 21 kb)

Supplementary Fig. 3

Positioning of the potential sites of a TCR/pMHC/CD8 nitration. (PDF 143 kb)

Supplementary Fig. 4

Effect of nitration of tyrosines in TCR and CD8 molecules. (PDF 127 kb)

Supplementary Fig. 5

Nitrotyrosine positive CD8+ T cells in lymphoid tissues. (PDF 59 kb)

Supplementary Fig. 6

Duration of CD8+ T-cell tolerance induced by MDSC. (PDF 16 kb)

Supplementary Fig. 7

Myeloid derived suppressor cells associate with T cells. (PDF 91 kb)

Supplementary Fig. 8

Effect of uric acid on T-cell activation in vivo. (PDF 67 kb)

Supplementary Discussion (PDF 59 kb)

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Nagaraj, S., Gupta, K., Pisarev, V. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13, 828–835 (2007). https://doi.org/10.1038/nm1609

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