Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer.
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.
Nagaraj
Srinivas
S
H. Lee Moffitt Cancer Center, University of South Florida, 12902 Magnolia Drive, Tampa, Florida 33647, USA.
Gupta
Kapil
K
Pisarev
Vladimir
V
Kinarsky
Leo
L
Sherman
Simon
S
Kang
Loveleen
L
Herber
Donna L
DL
Schneck
Jonathan
J
Gabrilovich
Dmitry I
DI
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*; D009374:Neoplasms, Experimental; D009566:Nitrates / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D009566:Nitrates; D011948:Receptors, Antigen, T-Cell