Critical role of Toll-like receptor signaling in NK cell activation

GUO Qie 0 ZHANG Cai ) 0 0 Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University , Jinan 250012, China Toll-like receptors (TLRs) and NK cell receptors are the most important receptor superfamilies in innate immunity. TLRs act as the sensor of external pathogens, while NK cells detect alterations in endogenous protein expression on target cells through activating and inhibitory receptors. Accumulating data has demonstrated that TLRs and NK cell receptors can coordinate and regulate each other during immune responses, which contributes to the initiation of innate response and the priming of adaptive responses. TLRs can activate NK cell function directly or with the help of accessory cells in a cytokine or cell-to-cell contact dependent manner. More understanding of the recognition of innate receptors and interactions between them may provide important insights into the design of effective strategies to combat tumor and microbial infections. In this review, we summarize how TLRs and NK cells discriminate the self or non-self components respectively. And importantly, we pay more attention to the role of TLR signaling in induction of NK cell activation, responses and the crosstalk between them. - The innate immune system in mammalian has evolved a universal and conservative defense line against the invasion from exotic micro-organisms and autogenous transformed objects. The early concept about innate immunity believed that it can nonspecifically eliminate microbes because innate immune cells exert their function without pre-sensitization; however, the discovery of Toll-like receptors (TLRs) in the mid-1990s showes that pathogen recognization by the innate immune system actually relies on germline-encoded pattern-receptors (PRRs) that have evolved to detect components of foreign pathogens, also known as pathogenassociated molecular patterns (PAMPs) [13]. So far four classes of PRRs have been identified: TLRs, RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and C-type lectin receptors (CLRs) [4]. Among them, TLRs have the most greatly advanced understanding of how they recognize conserved structures in pathogens and trigger innate immune response to further prime antigen-specific adaptive immunity. Natural killer (NK) cells are innate effector cells that play a critical role in immunosurveillance by eliminating virally infected and transformed cells via generating and secreting cytolytic granules or cytokines, as well as expressing several activating and inhibitory receptors on the surface [5]. Equally as the essential components of the innate immune system, NK cells and TLRs bear unique mechanism to sense dangerous signals and exert immune effect. On the other hand, they coordinate with each other to control the invasion of acataleptic challenges [6,7]. In this review, we survey how TLRs and NK cells discriminate the self and non-self components respectively. And importantly, we pay more attention to the present knowledge of how TLRs affect the function of NK cells and the crosstalk between them. TLRsThe sensors of external stimulator TLRs, acting as the sensors of external pathogens, are one of the most important PRRs. They are expressed on almost The Author(s) 2012. This article is published with open access at Springerlink.com all immune cells, such as DCs, monocytes, macrophages, T cell, B cell, NK cells, and even on non-immune cells such as fibroblasts, epithelial cells and some tumor cells [8]. Although TLRs are evolutionarily conserved from the worm Caenorhabditis elegans to mammals, the expression of TLRs is not stable but constantly variable in response to environmental stress such as virus or bacteria infection [9]. TLRs generally detect microbes-related components which are usually called PAMPs to activate transcriptional programs that initiate innate immune responses and orchestrate acquired antigen-specific resistance to exogenetic insults [10]. Stimulation of TLRs by these microbial products, such as lipids, lipoproteins, lipopolysaccharide (LPS) and nucleic acids, leads to the activation of signaling pathways that result in the up-regulation of antimicrobial genes and the secretion of some inflammatory cytokines or IFNs to start up the defense responses [11,12]. So far, over ten kinds of functional TLRs have been elucidated in mammals, including 10 in humans and 12 in mice respectively, with TLR1-TLR9 being conserved in both species [13]. These TLRs are roughly divided into two subfamilies depending on their cellular localization and respective PAMP ligands. One group is composed of TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11, which are expressed on cell surface and recognize mainly microbial lipids components such as LPS and lipoproteins; the other group mainly includes TLR3, TLR7, TLR8 and TLR9, which are expressed exclusively in intracellular vesicles such as endoplasmic reticulum (ER), endosomes, lysosomes and endolysosomes, where they recognize microbial nucleic acids components such as double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), unmethylated-CpG DNA motifs respectively [14,15]. So it is essential for these nucleic acid-sensing TLRs to internalize to the endosome before signaling is possible. Study of mice deficient with each TLR has demonstrated that each TLR has a distinct deflection in terms of PAMP recognition to perform their duty to counteract the extraneous invasion. For example, TLR4 stimulation with LPS is the main force to resist the Gram-negative bacterial infection. For recognition, TLR4 needs the presence of complex from CD14 and MD-2 in the assist of LPS-binding protein (LBP) [16]. For infection of Gram-positive bacteria, TLR2, rather than TLR4, plays a major role to clear away the pathogenic bacteria due to the deficiency of LPS. TLR2 forms heterodimers with TLR1 or TLR6 to recognize its ligands, the microbial components from Gram-positive bacterial, fungi, parasites and virus, including LTA, lipoproteins, and PG [17,18]. Moreover, some co-receptors on the cell surface can assist PAMP recognition of TLR2. These include CD36, which acts together with the TLR2-TLR6 heterodimer to mediate the sensing of some TLR2 agonists [19]; and dectin-1, a C-type lectin that binds to fungus -glucan and induces its internalization [20]. In addition to recognizing compounds derived from Gram-positive bacteria, TLR2 also binds LPS in the presence of LBP and CD14 and induces nuclear factor (NF)-B activation. LPS treatment has been demonstrated to enhance the oligomerization of TLR2. Concomitant with receptor oligomerization, the IL-1R-associated kinase is recruited to the TLR2 complex [21]. Viral structural components, including viral DNA, dsRNA, ssRNA, can activate nucleic acid-sensing TLRs, including TLR3, TLR7, TLR8 and TLR9 to eliminate the viral-invasion cells via inducing type I IFN and antiviral factors production [22]. Structurally, TLRs are type I trans-membrane proteins chara (...truncated)