Abstract
Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (TFH) cells that required ICOS co-stimulation was persistently restrained by PD-1 in vivo. These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor.
Highlights
T cell activation initiated by antigen-dependent signals through T cell receptors (TCRs) is tightly controlled by antigen-independent signals through stimulatory and inhibitory co-receptors to optimize beneficial immune responses while suppressing deleterious immune responses [1,2,3]
In order to confirm that programmed cell death 1 (PD-1) can inhibit the functional T cell activation upon TCR signal co-stimulated by inducible T cell co-stimulator (ICOS) in vivo, we examined the effect of PD-1 on the maintenance of follicular helper T (TFH) cells
The administration of anti-PD-L1 blocking Ab during the maintenance phase of TFH cells significantly increased the frequency and the number of TFH cells (1.0 vs. 1.5 % and 6.9 vs. 10.1 × 104 cells for control IgG- and anti-PD-L1 Ab-treated mice, respectively) (Figures 7B–E). These results suggest that the maintenance of TFH cells by TCR signal co-stimulated by ICOS is persistently weakened by PD-1 to restrict the number of TFH cells, which is in agreement with former reports that TFH cells with lower affinity were increased in the absence of PD-1 [45,46,47]
Summary
T cell activation initiated by antigen-dependent signals through T cell receptors (TCRs) is tightly controlled by antigen-independent signals through stimulatory and inhibitory co-receptors to optimize beneficial immune responses while suppressing deleterious immune responses [1,2,3]. Programmed cell death 1 (PD-1), one of the inhibitory co-receptors plays especially important roles in the regulation of autoimmunity, infectious immunity, and cancer immunity. PD-1 has been regarded to inhibit T cell activation by dephosphorylating these molecules by recruiting SHP-2, the recent report by Hui et al demonstrated that PD-1-bound SHP-2 dephosphorylated CD28 but not CD3ζ and inducible T cell co-stimulator (ICOS), another stimulatory co-receptor using a cell-free assay system, making the molecular target(s) of PD-1-bound SHP-2 controversial [14]
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