Mechanism of T cell tolerance induced by myeloid-derived suppressor cells

Srinivas Nagaraj, Adam G. Schrum, Hyun Il Cho, Esteban Celis, Dmitry I. Gabrilovich

Research output: Contribution to journalArticle

225 Citations (Scopus)

Abstract

Ag-specific T cell tolerance plays a critical role in tumor escape. Recent studies implicated myeloid-derived suppressor cells (MDSCs) in the induction of CD8+ T cell tolerance in tumor-bearing hosts. However, the mechanism of this phenomenon remained unclear. We have found that incubation of Ag-specific CD8+ T cells, with peptide-loaded MDSCs, did not induce signaling downstream of TCR. However, it prevented subsequent signaling from peptide-loaded dendritic cells. Using double TCR transgenic CD8+ T cells, we have demonstrated that MDSC induced tolerance to only the peptide, which was presented by MDSCs. T cell response to the peptide specific to the other TCR was not affected. Incubation of MDSCs with Ag-specific CD8+ T cells caused nitration of the molecules on the surface of CD8+ T cells, localized to the site of physical interaction between MDSC and T cells, which involves preferentially only TCR specific for the peptide presented by MDSCs. Postincubation with MDSCs, only nitrotyrosine-positive CD8+ T cells demonstrated profound nonresponsiveness to the specific peptide, whereas nitrotyrosine-negative CD8+ T cells responded normally to that stimulation. MDSCs caused dissociation between TCR and CD3ζ molecules, disrupting TCR complexes on T cells. Thus, these data describe a novel mechanism of Ag-specific CD8+ T cell tolerance in cancer.

Original languageEnglish (US)
Pages (from-to)3106-3116
Number of pages11
JournalJournal of Immunology
Volume184
Issue number6
DOIs
StatePublished - Mar 15 2010

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T-Lymphocytes
Peptides
Myeloid-Derived Suppressor Cells
Tumor Escape
Dendritic Cells
Neoplasms

ASJC Scopus subject areas

  • Immunology

Cite this

Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. / Nagaraj, Srinivas; Schrum, Adam G.; Cho, Hyun Il; Celis, Esteban; Gabrilovich, Dmitry I.

In: Journal of Immunology, Vol. 184, No. 6, 15.03.2010, p. 3106-3116.

Research output: Contribution to journalArticle

Nagaraj, Srinivas ; Schrum, Adam G. ; Cho, Hyun Il ; Celis, Esteban ; Gabrilovich, Dmitry I. / Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. In: Journal of Immunology. 2010 ; Vol. 184, No. 6. pp. 3106-3116.
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