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Review
. 2016 Mar 8;5(1):13.
doi: 10.3390/biology5010013.

Biochemical and Functional Insights Into the Integrated Regulation of Innate Immune Cell Responses by Teleost Leukocyte Immune-Type Receptors

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Free PMC article
Review

Biochemical and Functional Insights Into the Integrated Regulation of Innate Immune Cell Responses by Teleost Leukocyte Immune-Type Receptors

Chenjie Fei et al. Biology (Basel). .
Free PMC article

Abstract

Across vertebrates, innate immunity consists of a complex assortment of highly specialized cells capable of unleashing potent effector responses designed to destroy or mitigate foreign pathogens. The execution of various innate cellular behaviors such as phagocytosis, degranulation, or cell-mediated cytotoxicity are functionally indistinguishable when being performed by immune cells isolated from humans or teleost fishes; vertebrates that diverged from one another more than 450 million years ago. This suggests that vital components of the vertebrate innate defense machinery are conserved and investigating such processes in a range of model systems provides an important opportunity to identify fundamental features of vertebrate immunity. One characteristic that is highly conserved across vertebrate systems is that cellular immune responses are dependent on specialized immunoregulatory receptors that sense environmental stimuli and initiate intracellular cascades that can elicit appropriate effector responses. A wide variety of immunoregulatory receptor families have been extensively studied in mammals, and many have been identified as cell- and function-specific regulators of a range of innate responses. Although much less is known in fish, the growing database of genomic information has recently allowed for the identification of several immunoregulatory receptor gene families in teleosts. Many of these putative immunoregulatory receptors have yet to be assigned any specific role(s), and much of what is known has been based solely on structural and/or phylogenetic relationships with mammalian receptor families. As an attempt to address some of these shortcomings, this review will focus on our growing understanding of the functional roles played by specific members of the channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs), which appear to be important regulators of several innate cellular responses via classical as well as unique biochemical signaling networks.

Keywords: channel catfish; functional plasticity; immunoregulatory receptors; innate immunity; intracellular signaling; leukocyte immune-type receptors; phagocytosis; teleost; tyrosine-based signaling motifs.

Figures

Figure 1
Figure 1
Proposed inhibitory and stimulatory (Ictalurus punctatus) leukocyte immune-type receptors (IpLITR) 1.1b-mediated intracellular signaling events. Schematic representation of the proposed inhibitory (a) and stimulatory (b) signaling events mediated by IpLITR 1.1b in transfected cells. The cytoplasmic tail (CYT) region of IpLITR 1.1b contains six tyrosine residues (Y433, Y453, Y463, Y477, Y499, and Y503) that, when phosphorylated, serve as potential docking sites for various intracellular signaling adaptors. (a) In mouse natural killer (NK) cells, we demonstrated that engagement of IpLITR 1.1b caused a potent inhibition of NK cell-mediated cytotoxicity due to the recruitment of Csk-1 at Y453 (a1) or the binding of SH2 domain-containing cytoplasmic phosphatases (SHP) at Y477 and/or Y499, which are in immunoreceptor tyrosine-based inhibition motifs (ITIMs) (a2) [64,65]. The immunoreceptor tyrosine-based switch motifs (ITSM) located at Y503 may also recruit SHP phosphatases but this has not been examined. (b) IpLITR 1.1b engagement also induced phosphorylation of ERK1/2 and Akt as well as promoted phagocytosis in transfected rat basophilic leukemia (RBL)-2H3 cells [46]. These stimulatory effector cell functions could be mediated by the following mechanisms; (b1) direct recruitment of growth factor receptor-bound 2 (Grb2) to the YxN motif at Y463 may mediate the recruitment, and associated GEF activity, of SoS or the Gab2/class I PI3K (p85/p110) signaling complex. SoS is known to stimulate the accumulation of GTP-loaded Ras that would facilitate the stepwise phosphorylation of the Raf-MEK-ERK cassette. Alternatively, the Gab2 adaptor can localize class I PI3K activation to allow for targeted accumulation of the important signal transduction molecule phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3); (b2) ITIM-mediated recruitment of SHP-2 at Y477 or Y499, could recruit Grb2 and Gab2 allowing for the association of holomeric class I PI3Ks (p85/p110) leading to Akt phosphorylation and induction of phagocytosis. SHP-2-dependent recruitment of class I PI3Ks could also occur at the C-terminal ITSM located at Y503. SHP-2-dependent Grb2 recruitment may also trigger the SoS/Ras/Raf/MEK-dependent activation of ERK1/2; (b3) SH2D1A-mediated binding of PI3K (p85/p110) to the ITSM at Y503 is also possible. In general, class I PI3K activation can result in Akt phosphorylation or the recruitment of other PI(3,4,5)P3-dependent signaling proteins, including Vav, that are known to regulate phagocytosis. In addition, ITSM-mediated signaling can also recruit the adaptor EAT-2, closely related to SH2D1A, which is not shown here. For clarity, the role of signaling events dependent upon extracellular Ca2+ entry or intracellular Ca2+ mobilization have also been excluded.
Figure 2
Figure 2
Proposed mechanism for an ITAM-independent target acquisition and engulfment pathway facilitated by pLITR 1.1b. The unique short-circuited version of phagocytosis exhibited by IpLITR 1.1b-expressing cells likely requires that the proximal and distal regions of the IpLITR 1.1b CYT differentially participate in the recruitment and activation of select phagocytic effectors. Our results suggest that IpLITR 1.1b-mediated regulation of the actin polymerization machinery is dependent upon the catalytic activity of the Src and spleen tyrosine kinase (Syk) families of intracellular kinases [57]. We hypothesize that Src serves to place IpLITR 1.1b in a primed state that facilitates basal or constitutive coupling of IpLITR 1.1b to the minimal intracellular machinery required for target acquisition and phagocytic cup extension. In this model, the cytosolic adaptor non-catalytic region of tyrosine kinase adaptor protein 1 (Nck) is recruited to the consensus interaction motif H-I-Y-D-E-V located at Y433 in the proximal CYT region of IpLITR 1.1b. Nck has been shown to associate with the WAVE2 complex; a highly conserved pentameric heterocomplex that dynamically regulates Arp2/3-dependent actin polymerization [104]. Importantly, in mammalian cells, WAVE2 is expressed ubiquitously and found as a complex with four other proteins: Pir121, Nap1, Abi-1, and HSPC300 [104]. The mature WAVE2 complex is basally inactive and directly interacts with the SH3 domain of Nck through Nap1 [103,105]. Activation of the WAVE2 complex requires state-specific phosphorylation as well as interactions with GTP-bound Rho superfamily proteins, most commonly Rac [106]. As a result, we propose that the assembly of the Nck-WAVE2 complex within the proximal CYT region of IpLITR 1.1b could be coupled to recruitment of a stimulatory Rho-GEF within the distal CYT region. In particular, the spacing of the tyrosines in IpLITR 1.1b suggest that Syk could be recruited to two tandem ITIM motifs at Y477 and Y499 in the distal CYT region. Based on comparisons with other phagocytic receptors, we suspect that activation of the cytosolic Rho-GEF could be Syk-dependent. Syk activation of the Rho-GEF would provide the necessary catalyst for rapid actin-driven membrane protrusions via the WAVE2 complex. Together, this mechanism would encompass the minimal machinery required for PI3K-independent target capture pathway by IpLITR 1.1b.

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