Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer
Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer
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DOI：
10.1038/nm1609
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发表时间：
2007-07-01
期刊：
影响因子：
82.9
通讯作者：
Gabrilovich, Dmitry I.
中科院分区：
文献类型：
--
作者：
Nagaraj, Srinivas;Gupta, Kapil;Gabrilovich, Dmitry I.
髓系抑制细胞(MDSCs)诱导的抗原特异性CD8(+)T细胞耐受是肿瘤逃逸的主要机制之一。利用体内模型，我们发现MDSCs通过硝化T细胞受体(TCR)-CD8复合体中的酪氨酸，直接破坏特异性多肽-主要组织相容性复合体(PMHC)二聚体与CD8表达的T细胞的结合。这一过程使得表达CD8的T细胞无法结合pMHC并对特定的多肽做出反应，尽管它们保留了对非特异性刺激做出反应的能力。TCR-CD8的硝化是由MDSCs通过细胞与细胞直接接触时产生的过氧基团和过氧亚硝酸根的过量产生而诱导的。分子模拟表明，特定的硝化位点可能影响TCR-CD8的构象灵活性及其与pMHC的相互作用。这些数据确定了癌症中T细胞耐受的一种以前未知的机制，这也与许多与MDSCs积聚相关的病理情况有关。
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.