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XU Chenqi lab contributes a preview discussing PD-1’s role in T cell exhaustion
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PD-1, a well-established drug target for cancer immunotherapy, has been recognized as a driver of T cell exhaustion for long time but this concept is now challenged by a recently published paper at Molecular Cell by Okazaki and colleagues. XU Chenqi was invited by Molecular Cell to contribute a preview discussing these controversial data and proposing his own model of PD-1 function.
In the paper of Okazaki and colleagues, the authors used human and mouse T cell systems to study how PD-1 signaling impacts transcriptome at the early stage of T cell activation. They find PD-1 primarily affects genes that are induced or suppressed by strong TCR signaling, i.e. cytokine genes but not proliferation and exhaustion genes. This paper points out PD-1’s role at the early stage of T cell activation is controlling effector function but not inducing exhaustion. One needs to notice that PD-1 expression is only transient during normal T cell activation. Therefore, the new paper more reflects the function of transient PD-1 signaling. However, at the contexts of cancer or chronic infection, PD-1 expression is persistently induced by chronic antigen exposure. Persistent PD-1 signaling can work together with key transcription factors to induce and reinforce T cell exhaustion status.
In summary, PD-1’s role is different under different scenarios and its contribution to T cell exhaustion needs to be further studied.


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