Ageing and latent CMV infection impact on maturation, differentiation and exhaustion profiles of T-cell receptor gammadelta T-cells

Martine J Kallemeijn,Jan A N Verhaar,Jacques J M Van Dongen,Elisabeth Brouwer,Michèle Y Van Der Klift,Wayel H Abdulahad,Anne Mieke H Boots,Anton W Langerak

doi:10.1038/s41598-017-05849-1

Martine J Kallemeijn, Jan A N Verhaar + Show 6 more

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https://doi.org/10.1038/s41598-017-05849-1

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Abstract

Ageing is a broad cellular process, largely affecting the immune system, especially T-lymphocytes. Additionally to immunosenescence alone, cytomegalovirus (CMV) infection is thought to have major impacts on T-cell subset composition and exhaustion. These impacts have been studied extensively in TCRαβ+ T-cells, with reduction in naive, increase in effector (memory) subsets and shifts in CD4/CD8-ratios, in conjunction with morbidity and mortality in elderly. Effects of both ageing and CMV on the TCRγδ+ T-cell compartment remain largely elusive. In the current study we investigated Vγ- and Vδ-usage, maturation, differentiation and exhaustion marker profiles of both CD4 and CD8 double-negative (DN) and CD8+TCRγδ+ T-cells in 157 individuals, age range 20–95. We observed a progressive decrease in absolute numbers of total TCRγδ+ T-cells in blood, affecting the predominant Vγ9/Vδ2 population. Aged TCRγδ+ T-cells appeared to shift from naive to more (late-stage) effector phenotypes, which appeared more prominent in case of persistent CMV infections. In addition, we found effects of both ageing and CMV on the absolute counts of exhausted TCRγδ+ T-cells. Collectively, our data show a clear impact of ageing and CMV persistence on DN and CD8+TCRγδ+ T-cells, similar to what has been reported in CD8+TCRαβ+ T-cells, indicating that they undergo similar ageing processes.

Highlights

Ageing is a general cellular process, defined as the result of damage created by reactive oxygen species (ROS) during oxidative stress in mitochondria[1]
Many different markers for exhausted CD8+ cytotoxic T-lymphocytes (CTL) have been described, ranging from NK-cell markers such as CD5715–17, killer cell lectin-like receptor G1 (KLRG1)[13, 18, 19], and 2B4, known as CD24420–22, to cell death-associated markers such as Programmed cell death 1 (PD1) which is a marker of early exhaustion[23,24,25], and FAS (CD95)[13, 26]
The process of immunological ageing, including expression of the above markers has been extensively studied in TCRαβ+CD8+ T-cells, but less so in TCRγδ+ T-cells, which show functional overlap with the TCRαβ+CD8+ CTLs with respect to high levels of cytotoxicity[29], cytokine release – mainly IFN-γ and IL-17 based on antigen experience[30, 31], induction of inflammation, immunoregulation and cytoprotection upon antigen recognition

Summary

Introduction

Ageing is a general cellular process, defined as the result of damage created by reactive oxygen species (ROS) during oxidative stress in mitochondria[1]. Immunological ageing ( called immunosenescence) is defined at different levels: desensitization of dendritic cells (DCs) leading to reduced TLR responses, low bone marrow (BM) output of naive B-cells, insufficient T-cell help in the spleen and lymph nodes (LN), resulting in decreased memory B-cell expansions and antibody secretion, and decreased thymopoiesis in the thymus[5, 6]. A central feature in immunosenescence is involution of the thymus, which is characterized by thymic shrinkage and a significantly reduced naive T-cell output[5, 6, 12] This leads to a reduced T-cell dependent antigen-specific response and fewer interactions with other immune cell types, such as reduced help to B-cells in germinal centers[11]. Our data illustrate the impact of immunological ageing on TCRγδ+ T-cells, with a clear enhancing effect of CMV, as opposed to the more marginal contribution of CMV infection to increased TCRγδ+ T-cell exhaustion in elderly

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