PD-1 preferentially inhibits the activation of low-affinity T cells
PD-1 preferentially inhibits the activation of low-affinity T cells
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DOI：
10.1073/pnas.2107141118
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发表时间：
2021-08-31
影响因子：
11.1
通讯作者：
Okazaki，Taku
中科院分区：
文献类型：
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作者：
Shimizu，Kenji;Sugiura，Daisuke;Okazaki，Taku
抗pd -1疗法可以激活肿瘤特异性T细胞来破坏肿瘤。然而，对于不同抗原特异性和亲和力的T细胞是否以及如何受到PD-1的差异调节，我们仍然知之甚少。在抗原刺激下，多种基因在T细胞中被诱导。最近，我们发现诱导基因所需的T细胞受体（TCR）信号强度因基因而异，PD-1优先抑制需要更强TCR信号的基因的诱导。由于每个T细胞都有自己的反应特征，基因的诱导性可能在不同的T细胞中有所不同。因此，PD-1的抑制作用也有望在不同的T细胞中有所不同。在当前的研究中，我们研究了调节T细胞对抗原刺激反应的因素是否以及如何影响PD-1功能。通过分析与多肽- mhc复合物（pMHC）具有不同亲和力的TCR和与TCR具有不同亲和力的pMHC，我们发现当TCR:pMHC亲和力较低时，PD-1能有效抑制TCR诱导基因的表达。相比之下，多肽与MHC的亲和力和MHC的表达水平并不影响TCR诱导基因的PD-1敏感性，尽管它们通过改变pMHC的形成效率显著改变了T细胞的剂量反应性，这表明个体TCR信号的强度是PD-1敏感性的关键决定因素。因此，我们观察到pd -1缺陷小鼠在接种肿瘤细胞后，对肿瘤抗原低亲和力的T细胞优先扩增。这些结果表明，PD-1通过优先抑制低亲和力T细胞，对T细胞反应施加定性控制。
Anti–PD-1 therapies can activate tumor-specific T cells to destroy tumors. However, whether and how T cells with different antigen specificity and affinity are differentially regulated by PD-1 remain vaguely understood. Upon antigen stimulation, a variety of genes is induced in T cells. Recently, we found that T cell receptor (TCR) signal strength required for the induction of genes varies across different genes and PD-1 preferentially inhibits the induction of genes that require stronger TCR signal. As each T cell has its own response characteristics, inducibility of genes likely differs across different T cells. Accordingly, the inhibitory effects of PD-1 are also expected to differ across different T cells. In the current study, we investigated whether and how factors that modulate T cell responsiveness to antigenic stimuli influence PD-1 function. By analyzing TCRs with different affinities to peptide–MHC complexes (pMHC) and pMHCs with different affinities to TCR, we demonstrated that PD-1 inhibits the expression of TCR-inducible genes efficiently when TCR:pMHC affinity is low. In contrast, affinities of peptides to MHC and MHC expression levels did not affect PD-1 sensitivity of TCR-inducible genes although they markedly altered the dose responsiveness of T cells by changing the efficiency of pMHC formation, suggesting that the strength of individual TCR signal is the key determinant of PD-1 sensitivity. Accordingly, we observed a preferential expansion of T cells with low-affinity to tumor-antigen in PD-1–deficient mice upon inoculation of tumor cells. These results demonstrate that PD-1 imposes qualitative control of T cell responses by preferentially suppressing low-affinity T cells.