Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 6, Pages 1201-1217Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20112741
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [23113521]
- Japan Science and Technology Agency
- Grants-in-Aid for Scientific Research [24590590, 23249082, 24590591] Funding Source: KAKEN
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Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1-mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1-TCR colocalization within microclusters is required for efficient PD-1-mediated suppression. This inhibitory mechanism also functions in PD-1(hi) T cells generated in vivo and can be overridden by a neutralizing anti-PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.
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