Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Abstract

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.

CTC immune escape mediated by PD-L1

“…Studies have shown that Treg cells highly express PD-1 and PD-L1 [7][8]. This inhibits the formation of immunological synapse [9], weaken the activation of TCR and co stimulatory signals in activated T cells [10]. PD-1/PD-L1 can express in all kinds of cells, MDSC for example, which enhance the immune suppression.…”

Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy

“…21 Tumor-associated DC directly participate in proliferation of CTL inside the tumor. [22][23][24] Myeloid cells in tumor are also targets for Poly(I:C) in adjuvant therapy. 25 Less-inflammatory TLR3 adjuvant would more benefit for combination therapy with checkpoint blockades than Poly(I:C) in tumor microenvironment having T and tumor cells with PD-1/PD-L1 to further bolster therapeutic efficacy (which will be shown with mouse models elsewhere), in the context that check-point blockades exhibit high therapeutic potential to some tumor types in mouse and clinical tests.…”

Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS

“…Often these coinhibitory ligands and receptors are termed check-points and these are extensively described in accompanying reviews in this same issue. A critical functional aspect to be kept in mind to understand the balance between costimulatory and coinhibitory receptors is that such receptors control the stability and duration of the integrin-dependent cell-to-cell contact (13) and thereby the outcome of cognate antigen presentation.…”