of Science, University of Tunis El Manar, Tunis, Tunisia; dResearch Center on Aging, Graduate Program in Immunology, Faculty of Medicine and Health Sciences, Department of Medicine, University of Sherbrooke, Sherbrooke, QC, Canada
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Abstract
Aging is associated with changes in the immune system. Both (innate and adaptive) arms of the immune system are involved. Natural killer (NK) cells are part of the innate immune system. They participate in host defense by eliminating cells that are virally infected, transformed, or senescent. They are also able to modulate the adaptive part of the immune system. As all cells, NK cells are subjected to changes with aging, which affects both their phenotype and functions. Aging is associated with various latent chronic viral infections, and the most significant among them is CMV. It is difficult to distinguish between the influence of CMV infection and that of aging itself on the NK cell properties. Recently, NK cells have been shown to be an important player in vaccine efficacy, which is also decreased with aging. In this chapter, we describe age-related changes in NK cells and their possible influence on the efficacy of vaccination in old age.
© 2020 S. Karger AG, Basel
Introduction
In the elderly, infections such as influenza, pneumonia, or shingles are preventable by the use of adequate vaccines [1, 2]. The widely accepted paradigm is that vaccine efficacy is decreased with aging due to what is called immunosenescence and its corollary – inflammaging [3–5]. However, recent studies did not confirm this paradigm [6–9] as the recently introduced vaccine for herpes zoster had an efficacy of >80% even in older subjects aged over 80 years, and the same is true for some recently introduced new influenza vaccines. Vaccine efficacy depends on an efficient and coordinated function of the immune system [10, 11]. The immune system and its response to pathogens are divided into two parts, the innate and the adaptive, each with its own components of distinct immune cells and soluble mediators. They have separate functions but necessarily and closely collaborate with each other. Natural killer (NK) cells are included in the innate, less specific part of the system, along with neutrophils, monocytes/macrophages, and dendritic cells (DCs) [12, 13]. So far, most vaccination studies have been devoted to the investigation of the adaptive part of the immune response which was found to be changed with aging [1]. In this chapter, we will discuss NK cell subsets and functions, their changes with aging, and whether and how they could participate in the vaccine response [14–16], be it directly or through the modulation of other immune cell functions.
NK Cells
NK cells are innate lymphoid cells which play a major role in the defense of the organism against viral infections and malignancies and comprise around 10–20% of the total peripheral lymphocyte population [17–19]. They are able to kill cells presenting abnormal MHC signatures either because of intracellular (viral) infection or because of neoplastic transformation [20–22]. Moreover, very recently other functions of NK cells have been described, including a wider polyfunctional antimicrobial response, elimination of senescent cells, resolution of inflammation, and induction of adaptive immune responses [23–28]. This is occurring constitutively; however, they may also present some characteristics of the adaptive response [29, 30]. NK cells consist of a relatively wide range of subpopulations characterized by their surface markers including various receptors [31, 32].
NK Cell Phenotype
In humans, NK cells are identified by the expression of the common hematopoietic cell marker CD45 and the more specific glycoprotein designated as CD56 [21, 31]. They do not express CD3. It has been shown in humans that mature cytotoxic NK cells are also developing in situ from resident oligopotent CD34+CD45RA+ hematopoietic precursor cells in the lymph nodes and liver [21, 33, 34]. About 90% of circulating human NK cells express T-bethi, Eomeslo, CD56dim, and CD16hi characteristics that are considered as mature and highly cytotoxic [15, 35]. The remaining 10% of human PBMC-derived NK cells are T-bethi, Eomeshi, CD56bright, and CD16lo. This subpopulation of NK cells produces a lot of cytokines (notably including IFNγ and TNFα) and is less cytotoxic than the CD16bright, CD56dim predominant phenotype. A fine balance between activation or inhibition of NK cell responses depends on the expression and communication between type I Ig superfamily activating receptors (NKG2D) and type II C-type lectin inhibitory receptors (NKG2A/CD94) [36–38].
Tissue-specific NK cells express the above-mentioned molecules at various levels. Most tissues in humans contain more of the immature, cytokine-producing, CD56bright, CD16dim NK cells [39, 40]. These NK cells present in the spleen and liver express the C-X-C motif-containing chemokine receptor 6 (CXCR6) [41]. This chemokine receptor has a ligand CXCL16 which is implicated in the homing to and survival within the liver of NK cells at quiescent state [41]. Furthermore, in humans, these NK cells express the already mentioned T-bet and Eomes as well as the CD69 activation marker [15].
Recently, it has been demonstrated that a subpopulation of NK cells so called “memory-like NK cells” exist, bearing various receptors including NKG2C and CD57 (CD16bright, CD56dim, CD57+) [38]. It is of note that this population was