Mechanism of T cell tolerance induced by myeloid-derived suppressor cells.
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 CD3zeta molecules, disrupting TCR complexes on T cells. Thus, these data describe a novel mechanism of Ag-specific CD8(+) T cell tolerance in cancer.
Department of Immunology, H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Srinivas
S
Nagaraj
Adam G
AG
Schrum
Hyun-Il
HI
Cho
Esteban
E
Celis
Dmitry I
DI
Gabrilovich
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D019674:Genes, T-Cell Receptor beta / Q000276:immunology; D007942:Leukemia, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018984:Epitopes, T-Lymphocyte