NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

Harry Pickering,Megan Llamas,Mario Deng,Suphamai Bunnapradist,Alexander Hoffmann,Gemalene Sunga,Joanna M Schaenman,Maura Rossetti,Yumeng Sun,Subha Sen,Richard S Ahn,Janice Arakawa-Hoyt,David W Gjertson,Kenichi Ishiyama,Elaine F Reed,Rajesh Parmar,Lewis L Lanier

doi:10.1172/jci.insight.153175

Abstract

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28–CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28–CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

Highlights

Cytomegalovirus (CMV) infection in immunocompetent individuals is mostly asymptomatic [1], but the virus is controlled rather than cleared, leading to lifelong persistence [2]
In solid organ transplant (SOT), CMV viremia and symptomatic disease are associated with chronic graft dysfunction and rejection [12], and NK and CD8 T cell number and magnitude have been implicated in control of CMV post-transplant and graft outcome [13,14,15,16]
The proportion of living donors and frequency of rejection and graft status at 1-year post-transplant were equivalent between CMV polymerase chain reaction (PCR)+ and PCR- patients

Summary

Introduction

Cytomegalovirus (CMV) infection in immunocompetent individuals is mostly asymptomatic [1], but the virus is controlled rather than cleared, leading to lifelong persistence [2]. In SOT, CMV viremia and symptomatic disease are associated with chronic graft dysfunction and rejection [12], and NK and CD8 T cell number and magnitude have been implicated in control of CMV post-transplant and graft outcome [13,14,15,16]. For this reason, transplant recipients receive antiviral prophylaxis with additional routine screening for CMV DNA in the periphery to monitor control of infection [17]

Methods

Results

Discussion

Conclusion