Analyzing the effects of PD-1 on the transcriptome of T cells, Shimizu et al. showed that the genes that were less efficiently induced by TCR stimulation (i.e. required higher antigen concentration) were more sensitive to PD-1-mediated inhibition/downregulation; this subset included genes encoding cytokines and effector molecules. Genes that were more efficiently expressed following TCR stimulation were more resistant to PD-1-mediated inhibition; this subset included genes encoding survival and proliferation. Inducibility and sensitivity to PD-1 partially depended on CpG frequencies and transcription factor binding motifs in the promoter regions.
Targeted blockade of programmed cell death 1 (PD-1), an immune-checkpoint receptor that inhibits T cell activation, provides clinical benefits in various cancers. However, how PD-1 modulates gene expression in T cells remains enigmatic. Here we investigated how PD-1 affects transcriptome changes induced by T cell receptor (TCR) activation. Intriguingly, we identified a huge variance in PD-1 sensitivity among TCR-inducible genes. When we quantified the half maximal effective concentration (EC50) as the relationship between change in gene expression and TCR signal strength, we found that genes associated with survival and proliferation were efficiently expressed upon TCR activation and resistant to PD-1-mediated inhibition. Conversely, genes encoding cytokines and effector molecules were expressed less efficiently and sensitive to PD- 1-mediated inhibition. We further demonstrated that transcription factor binding motifs and CpG fre- quency in the promoter region affect EC50 and thus the PD-1 sensitivity of genes. Our findings explain how PD-1, dependent on the TCR signal strength, calibrates cellular transcriptomes to shape functional properties of T cell populations.