Table 1.

NK cell-mediated mechanisms in periodontitis. NK cell, natural killer cell; DC–dendritic cell; A.a.—Aggregatibacter actinomycetemcomitans; P.g.—Porphyromonas gingivalis; F.n.—Fusobacterium nucleatum; LPS—lipopolysaccharide; TLR4—Toll-like receptor; IgG2—immunoglobulin G2; IL-2—interleukin 2; IFN-ɣ—interferon gamma; TNF—tumor necrosis factor; CRACC—CD2-like receptor-activating cytotoxic cell; NCR-1, natural cytotoxicity triggering receptor 1; LFA-1—Leukocyte-function-associated antigen-1; KIR—killer-cell immunoglobulin-like receptor; CD—cluster of differentiation; gF—gingival fibroblast; and PB—peripheral blood.

Mechanism	Evaluation of the Influence	Study Design	Reference
NK cells may participate in local responses through cytotoxic and/or immunoregulatory mechanisms.	Proinflammatory through tissue damage	Human biopsies Cell cultivation Immunostaining	Komiyama et al. (1988) [54]
	Immunoregulatory through modulation of B-cell activity
Increased concentrations of NK cells before and decreased concentrations after periodontal therapy demonstrate that periodontitis represents an altering pathogenetic environment influencing NK cells.	Proinflammatory through upregulation and cytotoxic immunoreactive effects	Human biopsies Cell cultivation Immunostaining	Kopp et al. (1988) [55]
NK cells may have immunoregulatory functions in periodontal disease	Immunoregulatory through regulation of T-cell proliferation and suppression of B-cell immunoglobulin production	Human biopsies Cell cultivation Immunostaining	Cobb at al. (1989) [56]
Cytotoxicity was exclusively found in NK-enriched low-density large granular lymphocyte fractions after activation by LPS from A.a. without stimulating high levels of proliferation	Uncertain biological relevance	Lymphocytes from PB Human cell cultivation	Lindemann et al. (1989) [57]
NK cells seemed to be significantly elevated in the peripheral blood of patients with juvenile and rapidly progressive periodontitis	Proinflammatory through immuno-pathogenetic effects	Lymphocyte analysis from human PB Immunostaining	Celenligli et al. (1990) [58]
Exact nature of the role of NK cells needs further investigation	Uncertain biological relevance	Lymphocyte analysis from human PB Immunostaining	Afar at el. (1992) [59]
Leu-11b-positive cells (CD 16+ NK cells) appeared more frequently in severe forms of periodontitis	Proinflammatory through destructive reactions	Human biopsies Immunostaining	Fujita et al. (1992) [60]
In all of the investigated patients, cytotoxic effects of NK cells were enhanced	Proinflammatory through enhanced cytotoxic effects	Lymphocyte analysis from human PB Immunostaining	Firatli et al. (1996) [61]
Influence of NK cells and T cells in the diseased group is uncertain	Uncertain biological relevance	Lymphocytes from PB Cell cultivation Immunostaining	Mahanonda et al. (2004) [62]
A.a.–LPS–TLR4 interactions on dendritic cells initiate the pathway leading to the production of IFN-ɣ by NK cells in periodontitis; this results in high levels of IgG2	Proinflammatory through destructive effects via IFN-ɣ production induced by IL-12	Lymphocyte analysis from human PB Cell cultivation Immunostaining	Kikuchi et al. (2004) [63]
	Immunoregulatory through protective effects via IgG2 production
P.g.–DC–NK interactions can result in reciprocal activation and increase of cytokine production by both DCs and NK cells. NK cells may provide IFN-ɣ needed to induce the P.g.-specific IgG2 in periodontitis	Immunoregulatory through induction of IgG2 response	Lymphocyte analysis from human PB Cell cultivation PCR	Kikuchi et al. (2005) [64]
Higher levels of CD57+ NK cells in tissue with periodontal disease indicate pathological progress	Proinflammatory through cytotoxic effects	Human biopsies Immunostaining	Stelin et al. (2009) [65]
Bone loss in the presence of NCR1 after infection with F.n. F.n. triggers the secretion of TNF-α which is dependent on NCR1 and binds directly on NCR1.	Proinflammatory through secretion of TNF-α	Induction of experimental periodontitis in mice Murine cell cultivation Immunostaining	Chaushu et al. (2012) [66]
Increased CRACC induction in aggressive periodontitis and in response to infections with A.a. CRACC-mediated NK cell activation could lead to an accelerated course of tissue destruction in aggressive periodontitis	Proinflammatory through CRACC induction activated by dendritic cells and subsequent IL-12 signaling	Human biopsies Transcriptomic analysis Cell cultivation	Krämer et al. (2013) [67]
Substantive increase in expression of genes related to NK cell interactions with antigen-presenting cells in periodontal tissues	Proinflammatory through cell invasion of periodontal pathogens and autoimmunity	Tissue samples of rhesus monkeys Gene expression microarray analysis	Gonzalez et al. (2014) [68]
IL-15 (bone destructive factor) activated NK cells are responsible for the induction of osteoblast apoptosis	Proinflammatory through IL-15 activation	Murine cell cultivation Immunostaining Gene expression	Takeda et al. (2014) [69]
Tissue damage is not associated with the presence or absence of different KIR genes	Uncertain biological relevance	Lymphocytes from human PB Gene analysis	Mazurek-Mochel et al. (2014) [70]
KIR presence/absence polymorphism is not a significant factor involved in the pathogenesis of periodontitis in contrast to tobacco smoking	Uncertain biological relevance	Lymphocytes from human PB Gene analysis	Mazurek-Mochol et al. (2017) [71]
Numbers of NK cells were increased in the presence of gFs. GFs support the retention and survival of NK cells by LFA-1 expression	Uncertain biological relevance	Cell cultivation Immunostaining Gene analysis	Moonen et al. (2018) [72]