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

Helen M Parry,Guy Pratt,Jianmin Zuo,Archana Sharma-Oates,Wayne Croft,Francesca A M Kinsella,Jusnara Begum,Alexander C Dowell,Paul Moss,Kriti Verma,Luka Cicin-Sain

doi:10.1371/journal.ppat.1009349

Abstract

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.

Highlights

PD-1 is a member of the CD28 superfamily and is expressed widely on leucocyte populations [1]
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’

Summary

Introduction

PD-1 is a member of the CD28 superfamily and is expressed widely on leucocyte populations [1] Checkpoint proteins such as PD-1 and LAG-3 play an important physiological role in regulating the magnitude and function of the adaptive T cell immune response [2] and high levels of PD-1 expression are observed on exhausted T cells in the setting of cancer or chronic infection [3,4]. Despite the crucial therapeutic importance of PD-1 relatively little is known regarding its physiological role in the regulation of T cell function in healthy donors. This is true for CD4+ T cells and is noteworthy given increasing appreciation of the role of CD4+ T cells in tumour-specific immunity [6]. CMV reactivation is an important cause of morbidity and mortality in patients who are immune suppressed, such as primary fetal infection or transplant recipients, but the CMV-specific immune response is highly regulated across the life course and infection is not thought to have major clinical consequence for healthy immunocompetent individuals

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