CD3-CD56+ NK cells display an inflammatory profile in RR-MS patients
Introduction
Multiple Sclerosis (MS) is an immune-facilitated, chronic, neurodegenerative and demyelinating inflammatory central nervous system (CNS) disorder. The subgroups of MS are defined by the clinical course [1]. Relapsing-remitting (RR)-MS constitutes about 85–90% of MS patients and it occurs with acute attacks (relapses) and remissions [2]. The majority of MS patients initially present a single attack known as clinically isolated syndrome (CIS) [3]. Although the pathogenesis of MS is not well defined, autoreactive CD4+ T cells are thought to be responsible for attacking myelin antigens that cause tissue damage and inflammatory responses resulting in demyelination and neuronal damage [4,5]. Also, several studies revealed the contribution of the cells of innate immunity including Natural Killer (NK) cells in MS pathogenesis [6]. Because of the regulatory and cytotoxic functions of NK cells, their roles in MS pathogenesis has gained importance in recent years.
NK cells comprising 5–15% of leukocytes in healthy individuals are characterized phenotypically by the expression of CD56 but not CD3 molecule on their surface membrane. CD56 expression of NK cells is increased upon activation [[7], [8], [9]] suggesting CD56 as an activation marker [10] whereas immunosuppressive agents reduce their frequencies [11].
NK cells are well known by their cytolytic capabilities in early defense against tumor cells as well as pathogens, while having immunoregulatory properties through cytokine secretion revealing their importance in innate immunity [12]. Cellular functions of NK cells are governed by the balance between signals of activating and inhibitory receptors present on NK cells [13,14]. Activating receptors include NKG2D (Natural killer group 2, member D), 2B4 and the natural cytotoxicity receptors (NCRs) such as NKp30, NKp44 and NKp46. These receptors bind ligands induced by infection, tumors or cellular stress [15] and deliver activating signals to NK cells for cytotoxicity or cytokine secretion. NK cell activation is mainly regulated by the inhibitory receptors specific for MHC class I molecules [16]. Killer-cell immunoglobulin-like receptors (KIRs) and CD94-NKG2A heterodimer are the main groups of inhibitory MHC class I–specific receptors [17].
NK cells might be classified by their cytokine secretion profiles such as NK1, NK2 or NK22 cells. NK22 cells produce interleukin-22 (IL-22) upon stimulation with IL-12, IL-18 and IL-23 [18,19] whereas IL-27 suppresses the secretion of IL-22 from CD4+ T cells [20]. IL-22 is a pro-inflammatory cytokine with a protective role in the regeneration of epithelial tissues and host defence in mucosal barriers such as intestine, oral mucosa or lung [21]. There are also many studies demonstrating the possible contribution of IL-22 in neurological diseases [22]. However, contradictory findings were obtained from the studies investigating the involvement of IL-22 in autoimmune diseases [[23], [24], [25]]. IL-22RA2 was defined as a risk gene [26] and an inflammatory role was attributed to IL-22 in MS [27,28]. Recently, we have demonstrated a tendency to increase in IL-22 levels of NK cell subsets in RR-MS patients in response to cytokine stimulations [29]. However, the possible contribution of IL-22 in MS pathogenesis still needs to be elucidated.
In this study, to investigate the activation status of CD3–CD56+ NK cells in treated and untreated RR-MS in comparison with CIS patients, expression of NKG2A, NKG2D and NKp44 were analysed. In addition, plasma IL-22 levels as well as IL-22 content of CD3−CD56+ NK cells in response to IL-2, IL-10, IL-12 and IL-27 were measured for exploring the possible contribution of IL-22 in RR-MS pathogenesis.
Section snippets
Subjects
Istanbul University Cerrahpasa, Cerrahpasa Faculty of Medicine, Department of Neurology followed up the patients and directed them for enrollment to this study. This study was approved by Local Ethical Committee of Istanbul University Cerrahpasa, Cerrahpasa Faculty of Medicine, in compliance with Helsinki declaration and written informed consents were taken from all patients subsequent to their enrollment. The study group consisted of untreated (n = 9) and interferon-beta (IFN-β) treated (at
Ex vivo frequencies of NK cells and activating/inhibitory receptors
Peripheral blood samples obtained from patients were freshly stained for CD3 and CD56 molecules for detecting CD3−CD56+ NK cells (Fig. 1A) prior to measurement of their activating and inhibitory receptor expressions. Ex vivo CD3−CD56+ NK cell frequencies of treated RR-MS patients were significantly increased in comparison with untreated RR-MS patients (p = 0.019) although the percentage of CD3+ T cells were similar (Fig.1B).
In addition, the percentage of NKG2D+CD3−CD56+ NK cells of untreated
Discussion
As we have recently confirmed [29], IFN-β treatment was demonstrated to increase CD3−CD56bright NK cell subset frequencies of RR-MS patients in various studies [31]. In this study, total CD3−CD56+ NK cells of RR-MS patients were also shown to be increased following IFN-β treatment though CD3+ T cell frequencies did not vary between patient groups. This finding might indicate that IFN-β treatment directly affect NK cell ratio, regardless of whether CD3+ T cell frequencies decrease. To explore
Declaration of Competing Interest
All authors declare that they have no financial or non-financial competing interests.
Acknowledgments
We thank Erdem Tuzun, MD for critical reading of the manuscript. This study was funded by Scientific Research Projects Coordination Unit (BAP) of Istanbul University, Turkey (Project number: 18423) and The Scientific and Technological Research Council of Turkey (TUBITAK, Project number: 112S005).
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