Cytomegalovirus-Specific CD8+ T-Cells With Different T-Cell Receptor Affinities Segregate T-Cell Phenotypes and Correlate With Chronic Graft-Versus-Host Disease in Patients Post-Hematopoietic Stem Cell Transplantation.

Thomas Poiret,Rebecca Axelsson-Robertson,Ingemar Ernberg,Anurupa Nagchowdhury,Anna Von Landenberg,Mats Remberger,Olle Ringden,Markus Maeurer,Martin Rao,Xiao-Hua Luo

doi:10.3389/fimmu.2018.00760

Thomas Poiret, Rebecca Axelsson-Robertson + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2018.00760

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Abstract

Virus-specific T-cell responses are crucial to control cytomegalovirus (CMV) infections/reactivation in immunocompromised individuals. Adoptive cellular therapy with CMV-specific T-cells has become a viable treatment option. High-affinity anti-viral cellular immune responses are associated with improved long-term immune protection against CMV infection. To date, the characterization of high-affinity T-cell responses against CMV has not been achieved in blood from patients after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, the purpose of this study was to describe and analyze the phenotype and clinical impact of different CMV-specific CD8+ cytotoxic T-lymphocytes (CMV-CTL) classes based on their T-cell receptor (TCR) affinity. T-cells isolated from 23 patients during the first year following HSCT were tested for the expression of memory markers, programmed cell death 1 (PD-1), as well as TCR affinity, using three different HLA-A*02:01 CMVNLVPMVATV-Pp65 tetramers (wild-type, a245v and q226a mutants). High-affinity CMV-CTL defined by q226a tetramer binding, exhibited a higher frequency in CD8+ T-cells in the first month post-HSCT and exhibited an effector memory phenotype associated with strong PD-1 expression as compared to the medium- and low-affinity CMV-CTLs. High-affinity CMV-CTL was found at higher proportion in patients with chronic graft-versus-host disease (p < 0.001). This study provides a first insight into the detailed TCR affinities of CMV-CTL. This may be useful in order to improve current immunotherapy protocols using isolation of viral-specific T-cell populations based on their TCR affinity.

Highlights

Cytomegalovirus (CMV) is usually present in a latent state in a majority of the human population [1, 2]
The median time to onset of acute graft-versus-host disease (GVHD) and chronic GVHD was 30 and 145 days, respectively. 6 out of 23 patients died after hematopoietic stem cell transplantation (HSCT) (4 of them during the study time): three due to disease relapse and the other three patients due to HSCT-related complications
To understand the clinical impact of the CMV-CTL classes based on their T-cell receptor (TCR) affinity, we evaluated the correlation between clinical data and the findings mentioned above, i.e., CMV serostatus, GVHD and CMV reactivation, CMV-CTL affinity classes, and programmed cell death 1 (PD-1) expression

Summary

Introduction

Cytomegalovirus (CMV) is usually present in a latent state in a majority of the human population [1, 2]. CMV reactivation and disease have a direct impact on the outcome of the transplanted individuals, but is known to cause severe indirect effects, such as increased risk of bacterial and fungal infections [6] and increased incidence of graft-versus-host disease (GVHD) [7, 8]. Positive effects of CMV infection/reactivation have been reported, due to a promotion of graft-versus-leukemia effects by early CMV antigenemia ensuing immune responses, such as the cross-reactivity of γδ T-cells [9–12]. This relation remains controversial, since several studies did not observe a decreased risk of relapse concomitant with CMV reactivation [13–15]

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