T cell activation requires two signals: TCR signal and costimulatory signal (such as CD28), and T cell surface is also co inhibitory factor (such as PD-1), as a checkpoint to maintain immune homeostasis.
At present, most scientists believed that PD-1 blockade can reverse the failure of T cells (loss of function) by inhibiting TCR signal transduction, but not in the activation and effect or phase of T cell response. PD-1 blockade can also target the T cells which are not damaged, and they also play a role in the early stage of T cell
response and immune surveillance.
The researchers found that CD28 and PD-1 in the interaction of PD-1 and PD-L1 in the 30s in the vicinity of the TCR will be a short aggregation of the cluster, is conducive to the activation of PD-1 dephosphorylation of CD28. The combination of PD-1 and PD-L1 can lead to two kinds of tyrosine PD-1 cytoplasmic domain in (Y224 and Y248) in phosphate kinase Lck action, and then raised cytosolic tyrosine phosphatase SHP2 to PD-1 and CD28 dephosphorylation, and termination of CD28 signaling and regulating immune suppression function.
In the intact cell system, CD28 is preferentially phosphorylated in PD-1 activation compared to TCR, which indicates that PD-1 can inhibit the function of T cells by inactivating the CD28 signal.
At the same time, Professor Kamphorst also demonstrated that the CD28/B7 costimulatory pathway is required for effective PD-1 therapy and PD-1+ CD8 T cell proliferation in chronic viral infection and cancer mouse models.
After the activation of PD-1 can directly target the cytoplasmic region of CD28, and has a higher ratio of T cell receptor downstream molecular affinity, further emphasizes the interaction between CD28 and PD-1 pathways, PD-1 for molecular
targeted immunotherapy interactions provides new insights.
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T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition
1. Science 31 Mar 2017: