The CD300a inhibitory receptor belongs to the CD300 family of cell surface molecules that regulate a diverse array of immune cell processes. The inhibitory signal of CD300a depends on the phosphorylation of tyrosine residues embedded in ITIMs of the cytoplasmic tail. CD300a is broadly expressed on myeloid and lymphoid cells, and its expression is differentially regulated depending on the cell type. The finding that CD300a recognizes phosphatidylserine and phosphatidylethanolamine, two aminophospholipids exposed on the outer leaflet of dead and activated cells, has shed new light on its role in the modulation of immune functions and in its participation in the host response to several diseases states, such as infectious diseases, cancer, allergy, and chronic inflammatory diseases. This review summarizes the literature on CD300a expression, regulation, signaling pathways, and ligand interaction, as well as its role in fine tuning immune cell functions and its clinical relevance.

To preserve the identity and integrity of the host and, at the same time, be effective against offenses, a complex and delicate balance of stimulating and inhibitory signals is required to efficiently regulate the activation status of the immune system. Among several other mechanisms that accomplish this mission, this balance is achieved by signals that emanate from cell surface receptors with activating and inhibitory capabilities (13). Some of them are clustered in the genome as families that consist of paired receptors with activating and inhibitory functions. In general, the inhibitory receptors are characterized by the presence of one or more ITIMs in their cytoplasmic tail (1, 3), whereas the activating receptors have a transmembrane charged residue that allows the association with adaptor proteins carrying ITAMs or a PI3K-binding motif (YxxM) (1, 2).

The human CD300 multigene family has seven members, which are named alphabetically according to their location on chromosome 17. The mouse counterparts, also known as CLM, LMIR, and MAIR, are encoded by nine genes located on mouse chromosome 11, the syntenic region of human chromosome 17 (4, 5). Nonetheless, with the exception of the two ITIM-bearing receptors (CD300a and CD300f), the rest of the CD300 family members are not perfect functional orthologs (4, 5). All of the receptors of the CD300 family have an extracellular IgV-like domain. The activating members have a short intracellular tail, and the transmembrane domain associates with ITAM-containing adaptor proteins, such as DAP12 and FcεRIγ, whereas the inhibitory receptors have a long intracellular tail that carries ITIMs. In addition to the IgV-like domain, CD300g has an extracellular mucin-like domain, but it does not have a known intracellular signaling motif (4, 5). It was shown that CD300 family members have the potential to form homodimers and heterodimers, which implies that, in addition to the signal that emanates from each single receptor, the formation of heterocomplexes adds a new layer of intricacy to the signaling pathways of the CD300 family of receptors (6).

In this review, we focus on the biology and disease relevance of the inhibitory receptor CD300a, whose gene ranks at the top of the human genes that show evidence of positive selection, suggesting a need to maintain some critical function (7).

Transcripts encoding human CD300a were detected in cells from both the myeloid and lymphoid lineages (4, 5). Nonetheless, the cell surface expression of CD300a has been difficult to determine because the majority of available mAbs display cross-reactivity and recognize both CD300a and CD300c on the cell surface (810). These are paired receptors with inhibitory and activating properties whose extracellular domains exhibit >80% similarity at the amino acid level. Recently, specific anti-CD300a and anti-CD300c mAbs were generated (1113).

With regard to the lymphoid lineage, CD300a is expressed on the surface of all human NK cells (9, 14) and in subsets of T and B cells (8, 10, 1517). Human naive CD4+ T cells express low levels of CD300a, whereas effector/memory cells can be subdivided into CD300a+ and CD300a subsets, and regulatory T cells are CD300a. Memory CD300a cells tend to proliferate slightly less than do memory CD300a+ cells (8, 15), and the expression of CD300a is associated with Th1 cells that are more polyfunctional and, after stimulation, upregulate the T-box transcription factor eomesodermin, whereas the IL-17 single-producing CD4+ T cells are mostly CD300a (10, 15). In contrast, in human CD8+ T cells, CD300a expression is coupled to a more cytotoxic phenotype, suggesting that CD300a is mostly expressed on effector/memory cells, whereas naive CD8+ T cells express low levels of the receptor (17). Naive B cells express low levels of CD300a, whereas memory B cells and plasma cells express variable levels, and germinal center B cells are negative for CD300a cell surface expression (16). In the myeloid lineage, CD300a is detected on the surface of plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), monocytes, macrophages, neutrophils, eosinophils, basophils, and mast cells (13, 1825).

In humans, cell surface expression of CD300a is regulated by multiple stimuli. For example, in CD4+ T cells, stimulation with anti-CD3 plus anti-CD28 mAbs and Th1-differentiation conditions upregulate cell surface expression of CD300a, whereas TGF-β exhibits a negative regulatory effect (8, 15). These in vitro–obtained results are in agreement with the fact that TGF-β1 is required for the development of regulatory T cells, which are CD300a, and Th17 cells, which tend to be enriched in the CD300a subset (10, 15). On naive B cells, BCR and TLR9 stimulation, along with T cell help, failed to upregulate the expression of CD300a in vitro, although TLR9 stimulation alone was sufficient to increase the expression of the receptor in memory B cells (16). The differential effect of TLR9 on CD300a expression on naive versus memory B cells may be explained by the low expression of TLR9 on human naive B cells and/or the fact that it is not coupled to other signaling pathways at this developmental stage. In contrast, IL-4 and TGF-β1 are negative regulators of CD300a expression on memory B cells (16).

LPS, IFN-γ, hypoxia, and the hypoxia-mimetic agent desferrioxamine upregulate the expression of CD300a on monocytes (2628). However, these results should be re-evaluated in light of the finding that human monocytes significantly express CD300c on the cell surface, and the mAbs used in these studies recognized both CD300a and CD300c (12, 13). In neutrophils, LPS and GM-CSF treatment caused a rapid translocation of an intracellular pool of CD300a to the cell surface, contributing to the observed increased expression in response to those stimuli (18). It is quite conceivable that an intracellular pool of CD300a also exists in basophils, which translocates to the cell surface in <20 min upon cell stimulation through FcεRI (21, 25). In eosinophils, CD300a expression is also upregulated by hypoxia and GM-CSF, and the inhibition of hypoxia-inducible factor 1 abolished this upregulation (24). In pDCs, IFN-α production in response to TLR7 and TLR9 agonists downregulates the expression of CD300a (22), and the eosinophil-derived major basic protein and eosinophil-derived neurotoxin downregulate it on cord blood–derived mast cells (19).

Transcripts encoding mouse CD300a, also known as CLM-8 (29), LMIR-1 (30), and MAIR-I (31), are also found in cells of the lymphoid and myeloid lineages. On the cell surface, it is expressed on the majority of myeloid cells, including macrophages, mast cells, dendritic cells, and granulocytes. On lymphocytes, mouse CD300a is expressed on subsets of B cells, with higher expression on marginal zone B cells (2932). However, in contrast to human CD300a, it is not detected on the surface of unstimulated NK and T cells (31).

In mice, CD300a cell surface expression was detected on NK cells after stimulation with IL-12 (31), and peroxisome proliferator-activated receptor β/δ directly regulates the expression of the CD300A gene in macrophages (33). In vitro, IL-33, a cytokine that has a key role in initiating Th2 responses, upregulates the expression of CD300a and CD300f on eosinophils, and it only upregulates the expression of CD300a on bone marrow–derived mast cells. However, injection of IL-33 in the peritoneal cavity did not induce the expression of CD300a in any of the analyzed cell types in contrast to the IL-33–induced upregulation of CD300f in vivo (34). These results may explain the requirement of CD300f, but not CD300a, for IL-33–induced eosinophil and mast cell activation (34).

Several groups used CD300-Ig fusion proteins as a tool to identify cells expressing ligands for the CD300 molecules (13, 3538). An interesting finding was that CD300a-Ig binds to apoptotic/dead cells from distant species in a Ca2+-dependent manner, suggesting that this receptor binds evolutionarily conserved ligands (37, 38). Apoptotic/dead cells are characterized by changes in the plasma membrane, including the loss of phospholipid asymmetry (39). From the early stages of apoptosis, cells expose phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the outer leaflet of the plasma membrane (3943), which act as “eat-me” signals and lead to their engulfment by phagocytes (44, 45). The binding of CD300a-Ig to dead cells was blocked by milk-fat globule EGF-factor VIII (MFG-E8), a ligand for PS, and by duramycin, a ligand for PE (37, 38), suggesting that these two aminophospholipids are ligands for CD300a. Subsequent experiments that included a variety of techniques, such as surface plasmon resonance, ultracentrifugation, ELISA, and immunoblotting, confirmed the direct binding of CD300a-Ig to purified aminophospholipids and to PS- or PE-containing liposomes (37, 38). In addition, human CD300a-Ig exhibited a preference for binding PE over PS (38).

The functional recognition of purified PE was demonstrated in a reporter cell system expressing human CD300a-CD3ζ chimeric receptors (13, 38). However, the functional recognition of PS could not be detected. The apparent discrepancy between the binding results to liposomes and pure lipids and the functional results may be explained by the fact that CD300a has a stronger binding to PE than to PS. Moreover, the particular steric environment of the extracellular part of CD300a may also affect its binding to these aminophospholipids. To identify the residues that are involved in human CD300a binding to PS and PE, a molecular model was generated based on the crystal structure of T cell/transmembrane, Ig, and mucin (TIM)-4 complexed with PS (38, 46). The metal ion and a molecule of PS or PE were placed in positions corresponding to the PS bound to the TIM-4 structure in the crystal structure of CD300a (38, 47). The model showed that PE and PS interact with CD300a residues that form a cavity into which the hydrophilic heads of the lipids can penetrate (38). The structural model was validated by analyzing the binding of CD300a-Ig mutants to lipids and dead cells. A WLRD motif in human CD300a was shown to be very important for binding (38). A similar motif, WFND, is required for the TIM molecules that bind PS (46, 48, 49). The binding of mouse CD300a-Ig to PS immobilized on a membrane, but not to PE, was observed by some investigators (37), whereas others did not find any binding of mouse CD300a-Ig to any lipid immobilized on a membrane (35). The reason for the discrepancy in these studies is unknown.

Human CD300a has four tyrosine residues in its cytoplasmic segment. Three of those tyrosines are within consensus sequences for classical or canonical ITIMs (V/LxYxxL/V), and the fourth is part of a nonclassical or permissive ITIM (SxYxxI) (14, 50). In contrast, the cytoplasmic tail of mouse CD300a possesses two classical ITIMs, and a third tyrosine is within a tyrosine-based sorting motif (YVNL) that was shown to mediate endocytosis of the receptor upon cross-linking with mAbs (30, 31) (Fig. 1).

FIGURE 1.

Schematic representation of human and mouse CD300a inhibitory receptor. The intracellular signaling motifs for each receptor are indicated, and the described interaction with phosphatases is shown. CD300a recognizes the aminophospholipids PS and PE exposed on the outer leaflet of dead (and activated) cells. PC, phosphatidylcholine.

FIGURE 1.

Schematic representation of human and mouse CD300a inhibitory receptor. The intracellular signaling motifs for each receptor are indicated, and the described interaction with phosphatases is shown. CD300a recognizes the aminophospholipids PS and PE exposed on the outer leaflet of dead (and activated) cells. PC, phosphatidylcholine.

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Tyrosine phosphorylation of ITIMs is required for the transmission of the inhibitory signal (9, 51, 52), and site-directed mutagenesis experiments showed that the four ITIMs in human CD300a were important for the inhibitory function of this receptor, with the third plasma membrane–distal ITIM being the most essential (9, 51). Similarly, tyrosine residues within ITIMs are responsible for the inhibitory signal of murine CD300a (30, 52). The chimeric receptor killer cell Ig-like receptor (KIR)-CD300a, consisting of the extracellular domains of KIR2DL2 fused to the transmembrane and cytoplasmic segments of human CD300a, was used to investigate the kinase that phosphorylates CD300a ITIMs. The interaction of Jurkat cells expressing KIR-CD300a with target cells expressing HLA-Cw3, the KIR2DL2 ligand, resulted in phosphorylation of CD300a ITIMs by the Src tyrosine kinase Lck but not by ZAP-70 (51). It is reasonable to expect that another Src tyrosine kinase might phosphorylate the CD300a ITIMs in cells that do not express Lck.

Phosphorylated CD300a ITIMs are able to recruit different phosphatases, depending on the examined cell type and the method of stimulation. For example, treatment of human NK cells with the tyrosine phosphatase inhibitor sodium pervanadate induced tyrosine phosphorylation of CD300a and the subsequent association with both Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2 (14), whereas in IL-5- or eotaxin-activated human eosinophils, cross-linking of the receptor with mAbs recruited SHP-1 but not SHP-2 (23). In coprecipitation experiments, treatment of human cord blood–derived mast cells with pervanadate resulted in SHP-1 and Src homology region 2 inositol 5′ phosphatase (SHIP)-1, but not SHP-2, association with CD300a. Intriguingly, upon cross-linking of the receptor with mAbs, only SHIP-1 associated with CD300a in the same cell type (19). Furthermore, immunoprecipitation of CD300a from human mast cells that were treated with Kit-CD300a, a bispecific Ab fragment linking Kit with CD300a, induced its tyrosine phosphorylation and the recruitment of SHIP but not SHP-1 (53). Triggering of CD300a with mAbs induced weak phosphorylation of SHIP-1 on human basophils, but the phosphorylation status of SHP-1 and SHP-2 was not tested (21). In a mouse B cell line, coligation of the BCR with anti-mouse IgG and Fc-CD300a, a chimeric molecule consisting of the extracellular and transmembrane domains of FcγRIIB and the cytoplasmic domain of mouse CD300a, resulted in the association of the intracellular tail of CD300a with SHP-1, SHP-2, and SHIP (30). The three phosphatases were recruited upon pervanadate treatment in RBL-2H3 cells ectopically expressing mouse CD300a, but only SHP-1 and SHIP were recruited after cross-linking of the receptor with mAbs (52). In bone marrow–derived mast cells, mouse CD300a coimmunoprecipitated with SHP-1, SHP-2, and SHIP upon pervanadate treatment (30, 31). Finally, in a more physiological setting, SHP-1 recruitment to CD300a was observed when bone marrow–derived mast cells and macrophages were mixed with apoptotic cells and treated with LPS (37, 54). The binding to SHP-2 and SHIP was not tested.

In an effort to understand which phosphatase is responsible for the transmission of the inhibitory signal, wild-type and phosphatase-deficient DT40 B cells ectopically expressing human CD300a were used to ascertain the role of each one of the phosphatases previously described to bind CD300a-phosphorylated ITIMs. CD300a in SHP-2– and SHIP-deficient DT40 cells was still able to inhibit BCR-mediated signals, such as Ca2+ mobilization. However, in SHP-1–deficient cells, the CD300a-mediated inhibition was largely abolished, indicating a dominant role for this phosphatase (51). This was further confirmed by the use of Jurkat cells expressing the chimeric receptor KIR-CD300a. Although both SHP-1 and SHP-2 coimmunoprecipitated with KIR-CD300a after interaction with the ligand, only knocking down SHP-1 expression resulted in a decrease in the inhibitory potential of KIR-CD300a (51). The dominant role of SHP-1 was further demonstrated by knocking down SHP-1 expression in bone marrow–derived mast cells from CD300a-deficient mice. Although CD300a−/− mast cells produced significantly more TNF-α than did CD300a+/+ mast cells after stimulation with LPS in the presence of apoptotic cells, there was no significant difference in TNF-α production between SHP-1–knocked down CD300a+/+ bone marrow–derived mast cells and SHP-1–knocked down CD300a−/− bone marrow–derived mast cells (54).

An important and unresolved question is whether coligation of CD300a with the activating receptor is necessary for the inhibitory signal. Although experiments were performed with (9, 10, 14, 16, 51) and without (22, 23, 55) coligation, few publications have addressed this issue (19, 52). Some investigators demonstrated that coligation of CD300a with FcεRI is essential for the CD300a-mediated inhibitory signal (52). Instead, others showed that there is no requirement for the coligation of CD300a with the activating receptor for CD300a to inhibit the FcεRI-mediated activation signal, despite the fact that coligation increased the inhibitory effect (19, 53). Interestingly, the effect on mast cell survival did not change significantly when CD300a was coligated with Kit (19). Furthermore, it was shown that the bispecific Ab fragment Kit-CD300a was able to inhibit Kit-mediated signals in mast cells stimulated with stem cell factor (SCF), but the Ab fragment control IgG-CD300a did not have any inhibitory effect, suggesting that, at least in these settings, coligation of CD300a and Kit and/or cross-linking of CD300a is required for the inhibitory effect (53).

Before PS and PE were identified as CD300a ligands, its role in regulating immune functions was studied using mAbs. Hence, its engagement by agonist mAbs decreased NK cell–mediated cytotoxicity and inhibited IgE-dependent Ca2+ mobilization and mediator release from mast cells and SCF-mediated mast cell activation, differentiation, and survival, as well as IgE-induced basophil degranulation (9, 14, 19, 21, 25, 31, 53, 56). The mAb-mediated cross-linking of CD300a also reduces FcγRIIa-triggered reactive oxygen species production and Ca2+ flux in neutrophils (18), suppresses eosinophil survival, migration, and inflammatory mediator production triggered by eotaxin, IL-15, and GM-CSF (23), and LPS- and CpG-induced IL-8 secretion by myelomonocytic cell lines (55). Cross-linking of CD300a regulated type I IFN and TNF-α secretion by pDCs in response to TLR7 and TLR9 stimulation (22). Also, CD300a was identified as a regulator of transendothelial migration in a transcriptional profiling of human monocytes following their adhesion to and passage through the endothelial monolayer (57). CD300a expression levels were upregulated following transmigration, and engagement of the receptor with mAbs significantly reduced monocyte transendothelial migration. In contrast, small interfering RNA–mediated downregulation of CD300a increased their rate of migration. Upregulation of CD300a following transendothelial migration may prepare monocytes to terminate the actual transmigration after they get in contact with apoptotic cells at the site of inflammation (57). Cross-linking of CD300a with mAbs also regulated TCR-mediated and BCR-mediated signaling (10, 16).

Given that both PS and PE are expressed on dead cells (3945, 58), the relevance and significance of the interaction between CD300a and PE/PS were demonstrated by the role of this receptor in modulating the engulfment of dead cells (38, 54). In fact, CD300a downregulates the uptake of apoptotic cells by macrophages, and its ectopic expression in CD300a cell lines also decreased the clearance of dead cells (38). These results somehow alter the existing “eat-me” signal paradigm in that, during the death process when cells expose PE, they may provide a “don’t-eat-me-yet” signal after interacting with CD300a. CD300a−/− bone marrow–derived mast cells and macrophages treated with LPS in the presence of apoptotic cells produced higher levels of proinflammatory cytokines, indicating that CD300a acts as an inhibitory receptor in these cell types after interacting with PS and PE on apoptotic cells (54). Furthermore, PS-expressing tumor targets decrease NK cell–mediated cytotoxicity (11), and apoptotic cells and PS-containing liposomes inhibit IgE-induced basophil degranulation in a CD300a-dependent manner (59).

The role of the CD300 family of receptors in several pathologies, their possible usage as biomarkers, and the potential for targeting these molecules for therapeutic purposes have been well documented (4) over the course of the last years.

Viral infections.

To efficiently replicate, viruses, such as HIV, hepatitis C virus, and others, activate the host cells leading to an increase in intracellular calcium, which, in turn, causes externalization of PS and PE, the ligands of CD300a. Moreover, translocation of these two phospholipids to the outer leaflet of the plasma membrane is one of the earliest events associated with apoptosis induced by viruses, such as HIV. Recent reports suggested that exposure of PS, and probably also PE, inhibits inflammation and the immune response, allowing the virus to avoid recognition by the immune system (60). In fact, anti-PS Abs have the ability to inhibit HIV infection in vitro (61) and showed therapeutic potential in in vivo models of CMV and Pichinde virus infection (60). The expression of CD300a on circulating B cells is downregulated during HIV infection (16), suggesting the possibility that this inhibitory receptor may contribute to the B cell hyperactivation and dysfunction observed in HIV-infected patients (62). The decrease in CD300a expression on B cell subsets, with the exception of plasmablasts, was not corrected by effective antiretroviral therapy. In contrast, a significant positive correlation between CD4+ T cell count and CD300a expression on memory B cells was observed in patients whose viremia was controlled by antiretroviral therapy. Altogether, these results indicate that the altered CD300a expression on B cells during HIV infection is a complex process involving several factors. Also, a positive correlation between mRNA levels of CD300a and the expression of the transcription factor BATF in HIV-specific CD8+ T cells was reported (63). BATF expression is very high in CD8+ exhausted T cells, and it inhibits the function of HIV-specific cells through a mechanism that involves the increased expression of inhibitory receptors, such as CD300a (63).

A variety of viruses enclose their capsid in a lipid bilayer that can be obtained during virus budding from plasma membrane (64). Very importantly, this implies the incorporation of PS, and likely PE, into the viral envelope. The presentation of PS and PE on the outer leaflet of these membranes camouflages viruses as apoptotic bodies regulating cell entry through a process termed “apoptotic mimicry” (64). Consequently, viral envelope PS and PE are very important for enveloped viral replication, and it was demonstrated that enveloped viruses, such as dengue, vaccinia, West Nile, Sindbis, and Ebola viruses, use a PS-mediated viral entry mechanism after interacting with PS receptors (6571). Among the human PS-binding molecules, not all of them enhance virus binding to cells and facilitate their engulfment (64). TIM-1, TIM-4, Protein S, and Gas6 (which bridge PS-containing membranes to cells expressing the receptor tyrosine kinases Tyro3, Axl, and Mer) and MFG-E8 (which bridges PS-containing membranes to cells expressing integrins αvβ3 and αvβ5) enhance virus entry. In contrast, other PS-binding receptors, such as TIM-3, stabilin-1, stabilin-2, and BAI1, do not increase binding to pseudotyped lentiviral vectors. Interestingly, human CD300a increases virus binding but does not enhance their transduction (64, 70). This resembles the ability of CD300a to bind apoptotic cells; however, this binding does not induce phagocytosis of dead cells (38, 54). In fact, CD300a suppressed phagocytosis of apoptotic cells by human macrophages (38). Therefore, the resulting signals from the binding of CD300a to PS- (and PE)-containing virus envelope might suppress viral endocytosis, which would lead to abortive virus infection.

Sepsis.

Defective removal of dead cells has deleterious consequences for the host (44, 58). The nature of the immune response to cell death depends on which, where, and how cells die, as well as what immune cells interact with them (72). Variations in these parameters determine whether cell death is immunogenic, tolerogenic, or silent (72). It is quite possible that the CD300 family of receptors plays a central role in determining the outcome of the immune response when dead cells interact with different components of the immune system. Indeed, recently published data support this hypothesis (54, 73, 74). A large number of cells undergo apoptosis in the peritoneal cavity during mouse models of cecal ligation and puncture (CLP) peritonitis (75). In this model, mast cells play an important role (76), and the expression of CD300a on their cell surface controls chemokine production, as shown by the fact that CD300a-deficient peritoneal mast cells produced more chemoattractants, leading to increased neutrophil recruitment and better bacterial clearance. As a consequence, CD300a−/− mice showed prolonged survival after CLP peritonitis (54). Ab blockade of CD300a interaction with PS also prolonged survival after CLP in wild-type mice (54), indicating that CD300a regulates mast cell inflammatory responses to microbial infections.

Allergy.

The expression of CD300a on cell types, such as mast cells, eosinophils, and basophils, that have an important role in the initiation, regulation, and effector phases of allergic responses, along with its ability to downregulate their activity in response to diverse stimuli, led to the design of bispecific Ab fragments targeting CD300a, along with other receptors, with the goal of downregulating the function of these cells during disease conditions in mouse models. Bispecific Ab fragments specific for CD300a and c-Kit abrogated mast cell degranulation induced by SCF during cutaneous anaphylaxis (53). Another bispecific Ab fragment linking CD300a to IgE bound to FcεRI, and, therefore, specific for FcεRI-expressing cells (i.e., basophils and mast cells), was able to abolish allergic and inflammatory responses in OVA-induced acute experimental asthma and IgE-dependent passive cutaneous anaphylaxis (56). A third bispecific Ab fragment, targeting CD300a to CCR3 and specific for mast cells and eosinophils, was able to reduce eosinophil signaling in vivo, eosinophil and mast cell mediator release, bronchoalveolar lavage fluid inflammation, eosinophil-derived TGF-β1 in the bronchoalveolar lavage fluid, and lung remodeling. Very importantly, this Ab fragment also reversed lung inflammation in a model of chronic established asthma (77). Also, in a model of allergic peritonitis, neutralization of CD300a with specific mAbs resulted in a significant increase in inflammatory mediators and eosinophilic infiltration (19). In humans, it was shown that the basal expression of CD300a on basophils from birch pollen allergic patients was significantly lower than for healthy control individuals (25). Interestingly, apoptotic cells inhibited anti-IgE–mediated basophil degranulation in healthy donors more efficiently than in allergic patients, suggesting that CD300a cell surface levels are very important in regulating the threshold for inhibiting IgE-mediated signals (59). Along these lines, recent studies showing the effects of hypoxia on the expression of CD300a in human eosinophils (24) and monocytes (28) are important for understanding the behavior of these cell types in diseased tissues and shed light on their role in inflammatory conditions.

Autoimmune disorders and chronic inflammatory conditions.

The CD300 gene complex has been linked to PSOR2, a susceptibility locus for psoriasis, which may also overlap with loci for rheumatoid arthritis and atopic dermatitis (78, 79). A single nucleotide polymorphism that encodes for a nonsynonymous polymorphism (R94Q) within the Ig domain of CD300a was associated with susceptibility to psoriasis (78); however, other studies disputed this linkage. Still, CD300a-Ig with arginine at position 94 binds better to dead cells, PE, and PS than does CD300-Ig with glutamine at position 94 (38), highlighting the relevance of this polymorphism. Interestingly, the surface expression of CD300a on CD4+ T cells is significantly lower in psoriatic patients compared with healthy controls (8); however, the Ab used in this latter study recognized both CD300a and CD300c. Although CD300c is not expressed on the surface of CD4+ T cells of healthy subjects (12, 13), it is not known whether it would be expressed in psoriatic patients.

CD300A was proposed, in combination with three other genes (KPNA4, IL1R2, and ELAVL1), as a biomarker that can help to differentiate ulcerative colitis from Crohn’s disease and noninflammatory diarrhea (80). This may benefit the serologic testing for inflammatory bowel disease, which only has sensitivity and specificity ∼80%, to differentiate Crohn’s disease from ulcerative colitis; it is based on reactivity to bacterial Ags and not host gene expression (81). When fed a high-fat diet, mice lacking CD300a develop chronic intestinal inflammation with expanded mesenteric lymph nodes and decreased numbers of intestinal capillaries (33). This leads to triglyceride malabsorption and reduced body weight. In CD300a−/− animals that are on high fat diet, peritoneal macrophages are M1 activated and produce higher levels of IL-6 in response to LPS. These results suggest that CD300a-mediated inhibitory signals have the ability to suppress chronic intestinal inflammation.

Cancer.

CD300a was identified, along with other markers, to be differentially expressed in acute lymphoblastic leukemia (ALL) compared with normal CD19+CD10+ B cell progenitors (82). Sixteen differentially expressed markers, including CD300a, were validated for minimal residual disease detection by four-color flow cytometry analysis (82). More recently, it also was reported that pre-B cell–derived ALL expresses high levels of CD300a and other ITIM-containing receptors, such as LAIR1 and PECAM1. Importantly, patients who had higher expression levels of these receptors at the time of diagnosis exhibited shorter overall and relapse-free survival, suggesting the potential use of these receptors as biomarkers for the stratification of patients with ALL (83). Furthermore, mouse genetic studies demonstrated that CD300a, PECAM1, and LAIR1 calibrate oncogenic signaling strength through recruitment of SHP-1 and SHIP-1, indicating that targeting of CD300a, as well as other inhibitory receptors, could be a strategy to treat ALL (83).

A recent study reported that the interaction between CD300a and PS inhibits tumor cell killing by NK cells (11). Several studies showed that, in the tumor microenvironment, there is a significant stress imposed on the tumor endothelium by acidity, reactive oxygen species, and transient hypoxia, which result in the redistribution and exposure of PS and PE (84). Indeed, expression of PS was detected in gastric carcinoma (85), ovarian carcinoma (86), and melanoma (87). Recent data support that the binding of CD300a-Ig to tumor cells is reduced when PS is blocked and that the blocking of PS enhances NK cell–mediated cytotoxicity. Blocking of PS partially restored NK cell cytotoxicity, indicating that tumor cells express an additional ligand for CD300a (11). This additional ligand might be PE, which also was shown to be a ligand for CD300a (13, 38). Therefore, a new tumor immune-evasion mechanism was suggested to be mediated through the interaction between PS and PE on tumor cells and CD300a on cytotoxic lymphocytes.

CD300a-mediated signaling is a very complex process that involves many players. More studies are required to define the targets of the phosphatases involved in the CD300a signaling pathway and the unique downstream signaling components. Little is known about the topology of PS and PE exposed on apoptotic cells and how they are engaged by specific receptors, including CD300a. Furthermore, there is no information on whether CD300a recognizes PS and PE as monomers, dimers, or higher-order oligomers and whether it is able to recognize these lipids in cis, as well as in trans. In a model of thioglycollate-induced peritonitis, it was shown that oxidation products of PE exposed on the plasma membrane of resident macrophages maintain self-tolerance by blocking phagocytosis of apoptotic cells by the freshly recruited inflammatory monocytes (88). Although it was proposed that the PS-binding molecule MFG-E8 has a role in this process (88), it also would be very interesting to study the role of CD300a in this model, as well as to elucidate whether the oxidation status of PE affects its binding to CD300a. Another fascinating question is the physiological relevance of lipid recognition by CD300a expressed on lymphocytes (i.e., NK cells, CTLs, subsets of CD4+ T cells, and memory B cells). So far, studies demonstrated the ability of CD300a to deliver inhibitory signals in lymphocytes, but future studies addressing the role of CD300a in key immune functions, such as cell differentiation, Ag presentation, cytokine production, cell-mediated cytotoxicity, termination of the immunological synapse, and so forth, are warranted. We are at the starting point in understanding the role of CD300a in disease settings and its potential as a therapeutic target. In light of the in vitro clinical data and preclinical data obtained from mouse models, we need to know more about the involvement of CD300a in human diseases, such as cancer, viral infections, sepsis, and autoimmune, inflammatory, and allergic diseases. Through its binding to PS and PE, CD300a is able to recognize the viability and activation status of cells and, consequently, have a significant influence on the final outcome of the immune response.

This work was supported by the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Gobierno de España (PI13/00889); the Marie Curie Actions, Career Integration Grant, European Commission (CIG 631674); and SAIOTEK, Departamento de Desarrollo Económico y Competitividad, Gobierno Vasco (SAIO13-PE13BF005).

Abbreviations used in this article:

ALL

acute lymphoblastic leukemia

CLP

cecal ligation and puncture

KIR

killer cell Ig-like receptor

mDC

myeloid dendritic cell

MFG-E8

milk-fat globule EGF-factor VIII

pDC

plasmacytoid dendritic cell

PE

phosphatidylethanolamine

PS

phosphatidylserine

SCF

stem cell factor

SHIP

Src homology region 2 inositol 5′ phosphatase

SHP

Src homology region 2 domain-containing phosphatase

TIM

T cell/transmembrane, Ig, and mucin.

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The authors have no financial conflicts of interest.