PD-1 is imprinted on cytomegalovirus-specific CD4+ T cells and attenuates Th1 cytokine production whilst maintaining cytotoxicity

PD-1 is expressed on exhausted T cells in cancer patients but its physiological role remains uncertain. We determined the phenotype, function and transcriptional correlates of PD-1 expression on cytomegalovirus-specific CD4+ T cells during latent infection. PD-1 expression ranged from 10–85% and remained stable over time within individual donors. This ‘setpoint’ was correlated with viral load at primary infection. PD-1+ CD4+ T cells display strong cytotoxic function but generate low levels of Th1 cytokines which is only partially reversed by PD-1 blockade. TCR clonotypes showed variable sharing between PD-1+ and PD-1- CMV-specific cells indicating that PD-1 status is defined either during T cell priming or subsequent clonal expansion. Physiological PD-1+ CD4+ T cells therefore display a unique ‘high cytotoxicity-low cytokine’ phenotype and may act to suppress viral reactivation whilst minimizing tissue inflammation. Improved understanding of the physiological role of PD-1 will help to delineate the mechanisms, and potential reversal, of PD-1+ CD4+ T cell exhaustion in patients with malignant disease.
Author summary PD-1 is expressed by a subset of CMV-specific CD4 T cells, we show expression is not associated with activation or ‘exhaustion’. We go onto show the size of the PD-1+ pool is established at primary infection, and expression remains stable on antigen specific cell populations and on individual cells, indicating expression is imprinted and controlled by a ‘set point’. PD-1 expressing CD4 T cells comprise cells with strong cytotoxicity but reduced cytokine production which may act to suppress viral reactivation whilst minimizing tissue inflammation.