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

234 Scopus citations

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
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this