Stem cell-like CD8+ T cells lacking PD-1 adapt to chronic stimulation by reducing TCR signaling and self-renewal capacity [RNA-seq]

CD8+ T cells responding to chronic viral infection adapt to continuous antigenic stimulation by the upregulation of inhibitory receptors. Here we addressed how memory-like CD8+ T cells (TML), which sustain the immune response in chronic infection due to their stem cell-like properties, adapt to chronic stimulation when they cannot express the co-inhibitory receptor PD-1. We found that PD-1 deficient TML cells did not show evidence of a compensatory increases in the expression of other inhibitory receptors or exhaustion-related genes. Rather, these cells displayed a reduced ability to activate multiple signaling pathways downstream of the TCR. By-passing proximal TCR signaling events restored the activation of PD-1-deficient TML cells. Consistent with reduced TCR signaling, PD-1-deficient TML cells had a reduced ability to expand and self-renew in response to recall stimulation. Transient blockade of PD-1/PD-L1 interaction similarly reduced the stemness of TML cells. Thus, in the absence of PD-1, stem-like CD8+ T cells adapt to chronic stimulation by reducing the capacity of the TCR to transmit activating signals, which limits the stemness of these cells. Thus, PD-1 preserves the stemness of TML cells ensuring the long-term maintenance of the immune response to chronic infection. Overall design: We transferred wild type (WT) or Pdcd1-/- (PD-1 KO) CD8+ T cells expressing a TCR specific for the LCMV epitope gp33-41 (P14 cells) (CD45.2) into Vbeta5 mice (CD45.1) prior to infection with LCMV cl13. Naive, TML and TEX cells were flow sorted based on their Tcf7-GFP and subjected to bulk RNAseq. The bulk RNAseq experiment also included the corresponding P14 subsets fromWT mice subjected to PD-L1 blockade. Two biological replicates were included for each sorted population.