Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101680


Historical Background

Immunoreceptor tyrosine-based inhibitory motif (ITIM) was first described in 1995. This conserved motif consists of six amino acids (S/I/V/LxYxxI/V/L) located in the cytoplasmic portion of certain transmembrane receptors (Daeron et al. 1995). Proteome-wide analysis identified 109 human ITIM-containing receptors (Staub et al. 2004). Conformational changes induced by ligand binding results in Src kinase-mediated phosphorylation of tyrosine in the ITIM, which in turn leads to the recruitment of SH2 domain-containing phosphatases. The ITIM-containing receptors bind tyrosine phosphatases SHP-1 or SHP-2 with the exception of immunoglobulin (Ig) G Fc receptor II-B (FcγRIIB), which only recruits the inositol-phosphatase SHIP. The first amino acid of ITIM affects binding specificity; isoleucine at the first position (IxYxxL/V) favors SHP-1 binding, whereas leucine (LxYxxL/V) favors SHIP. Phosphatase activation usually inhibits immune cell activation. Therefore these receptors are classified as immune inhibitory receptors. The downstream signaling of ITIM remains largely undefined, although known substrates of SHP-1 include the activated immunoreceptor tyrosine-based activation motif (ITAM), spleen tyrosine kinase (Syk), Src, zeta-chain associated protein kinase 70-kDa (ZAP70), Lck/Yes-related novel protein tyrosine kinase (Lyn), phosphatidylinositol-4-phosphate 3-kinase (PI3K), phospholipase C gamma (PLC-γ), and Vav 1 guanine nucleotide exchange factor (Vav1).

In contrast to the immune inhibitory ITIM, the activated immunoreceptor tyrosine-based activation motif, abbreviated ITAM, results in immune activation. The ITAM has a conserved amino acid sequence of YxxL/Ix(6–8)YxxL/I and is located in the cytoplasmic tail of membrane proteins. ITAM transmits signals from various membrane receptors including B cell receptors, T cell receptors, activating leukocyte Ig-like receptors (LILRs), certain activating natural killer (NK) cell receptors, and Fc receptors to name a few. Like ITIM-containing receptors, ligand binding of the ITAM-related receptor triggers Src kinase-mediated tyrosine phosphorylation within the ITAM, followed by recruitment and activation of tyrosine kinases (Syk in myeloid cells or ZAP-70 in lymphoid cells), usually resulting in immune activation.

The leukocyte Ig-like receptor subfamily B (LILRB) is a group of type I transmembrane glycoproteins with extracellular Ig-like domains that bind ligands and intracellular ITIMs. This important group of ITIM-containing receptors contains five members, LILRB1 to LILRB5, also called CD85J, CD85D, CD85A, CD85K, and CD85C, respectively, or leukocyte Ig-like receptors (LIR1, LIR2, LIR3, LIR5, and LIR8, respectively). LILRBs 1–4 were also named Ig-like transcripts (ILT2, ILT4, ILT5, and ILT3, respectively). Several LILRBs were cloned in 1997 (Borges et al. 1997; Colonna et al. 1997; Cella et al. 1997; Samaridis and Colonna 1997). In 2001, the names LILRB and LILRA were officially given to the inhibitory receptors and the activating receptors, respectively (Martin et al. 2002). These receptors are encoded in a region called leukocyte receptor complex at chromosomal region 19q13.4 in human (Borges et al. 1997; Wende et al. 1999). The domain organizations of the LILRBs are depicted schematically in Fig. 1a.
LILRB, Fig. 1

(a) Human LILRBs (b) mouse LILRB orthologs

LILRBs are primate and human specific, with only two mouse orthologs, paired immunoglobulin-like receptor B (PirB) (Kubagawa et al. 1997) and gp49B1 (Katz et al. 1996), known so far (Fig. 1b). Due to rapid evolution of LILRBs, animal models are of limited value, and the biological function and clinical significance of these receptors are not well understood. LILRBs were reported to be predominantly expressed in hematopoietic lineage cells and to suppress activation of various types of immune cells. LILRBs expressed on osteoclasts were reported to regulate osteoclastogenesis, and LILRB2 on hematopoietic stem cells (HSCs) supports ex vivo expansion of HSCs. LILRBs expressed on neurons regulate axon regeneration and have been implicated in neuropathology of Alzheimer’s disease. Because the immune-suppressive function of LILRBs is similar to that of immune checkpoint proteins such as CTLA4 and PD-1, LILRBs are considered to be immune checkpoint factors. Importantly, several groups including ours recently showed that LILRBs and a related ITIM-containing receptor LAIR1 are expressed on and have tumor-promoting functions in various hematopoietic and solid cancer cells. Therefore, in addition to the role in immune checkpoints, which is indirectly tumor-supportive, LILRBs are also capable of directly sustaining cancer development. There are recent reviews and articles about structural, functional, and genetic features of LILRBs and related molecules (Hirayasu and Arase 2015; Takai et al. 2011; Katz 2006; Barrow and Trowsdale 2008; Trowsdale et al. 2015; Kang et al. 2015, 2016; Kim et al. 2013; Zheng et al. 2012; Chen et al. 2015).

Ligands for ITIM-Containing Receptors

Known ligands for ITIM-containing receptors can be roughly divided into three groups: membrane-bound proteins (e.g., major histocompatibility complex (MHC) Class I or human leukocyte antigen (HLA) Class I molecules for LILRB1, 2, and 5), extracellular matrix proteins (collagens for LAIR1), and soluble proteins (e.g., antibodies for FcγRIIB). Some of the ligands and signaling pathways for LILRBs have been identified but many uncertainties remain. LILRB1 and LILRB2 bind classical and nonclassical MHC molecules. Several non-MHC or non-HLA ligands also bind to LILRBs 1 and 2, including S100A8 and S100A9 for LILRB1, and CD1d, several angiopoietin-like proteins (Angptls), oligomeric β-amyloid, myelin inhibitors reticulon 4 (RTN4, Nogo66), myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) for LILRB2. No ligands have been identified for LILRB3 or 4. Relatively little is known about LILRB5, but, recently, evidence that HLA-Class I heavy chains are LILRB5 ligands was reported. The known ligands for PirB, the mouse ortholog of LILRB2/3, include MHC class I and Angptls. gp49B1, the mouse ortholog of LILRB4, reportedly interacts with mouse integrin αvβ3. Human integrin αvβ3 does not bind to LILRB4, however. What is known about LILRBs ligands is summarized in Fig. 1.

Individual Human LILRBs and Mouse Orthologs


LILRB1 (also known as CD85J, ILT2, LIR1, and MIR7) has four ITIMs on the cytoplasmic side, and its extracellular portion has four immunoglobulin domains. LILRB1 is the most widely distributed of the LILRBs with expression on certain NK cells, monocytes/macrophages, eosinophils, basophils, dendritic cells (DCs), subsets of T cells, B cells, decidual macrophages, progenitor mast cells (but not mature mast cells), and osteoclasts. LILRB1 is expressed uniformly on monocytes and B cells, but the expression of LILRB1 on NK cells varies between individuals due to a significant degree of diversity within the LILRB1 locus, promoter choice, and translational repression. Various ligands are known to interact with LILRB1, including HLA class I molecules (e.g., HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G) with affinities in μM range. Of note, LILRB1 binds more strongly to HLA-G than to classical HLA class I molecules, and dimerized HLA-G induces more efficient LILRB1 signaling than the monomeric form. LILRB1 also binds UL18, an HLA class I homolog that is encoded by human cytomegalovirus with more than 1000-fold higher affinity than that for regular HLAs. LILRB1 interacts with the α3 domain and β2-microglobulin of class I proteins and the analogous region of UL18 but does not bind HLA-B27 lacking β2-microglobulin. In addition, S100A8 and S100A9, two calcium-binding proteins, interact with LILRB1.

Activation of LILRB1 transduces a negative signal that downregulates the immune response and cytotoxicity, exerting inhibitory effects on NK cells, monocytes/macrophages, DCs, T cells, B cells, osteoblasts, and other cells. However, LILRB1 was also reported to be an activating receptor in NK cells, macrophages, DCs, T cells, and some cancer cells under certain contexts.

NK cells. LILRB1 expressed on NK cells can inhibit immune activity of these cells. The binding of HLA-G to LILRB1 upregulates LILRB1 expression in NK cells, antigen-presenting cells, and T cells, and the ligand/LILRB1 interaction inhibits the polarization of NK-cell lytic granules by blocking accumulation of microtubule organizing center and F-actin at the area of contact, intracellular Ca2+ mobilization, and IFN-γ production. HLA-G binding to LILRB1 on NK and macrophages also inhibits cytotoxicity and inflammation toward trophoblasts, circumventing undesired antifetus immune responses during pregnancy. LILRB1 also regulates roles of NK cells in cancer immunotherapy. With the progression of breast cancer, the expression of LILRB1 on NK cells increases with concomitant decrease in functions of NK cells. Blockage of LILRB1 can restore the cytotoxicity function of NK cells in triple negative breast cancer. LILRB1 may act cooperatively with other receptors, such as killer cell Ig-like receptor (KIR) in NK cell line NK92, to exert inhibitory effects. Inhibition of both NKG2A and LILRB1 induce significant killing of AML and ALL cells by resting KIR-deficient NK cells, suggesting that NKG2A, LILRB1, and KIR might be promising NK cell targets for treatment of acute leukemias. Interestingly, LILRB1 may also mediate activating signaling through its immunoreceptor tyrosine-based switch motif (ITSM). NK cell-mediated inhibition of HIV-1 replication in monocyte-derived DCs is mediated by the interaction between LILRB1 on the NK cells with S100A9, a non-HLA class I calcium-binding protein, which is expressed on the DCs.

Monocytes/macrophages. LILRB1 can inhibit monocyte activation signals. The binding of HLA-DR to LILRB1 inhibits Ca2+ mobilization in monocytes. Coligation of LILRB1 with Fc receptor I (CD64) decreases tyrosine phosphorylation of the Fc receptor γ chain and Syk molecules and inhibits intracellular Ca2+ mobilization. The expression of LILRB1 decreases in activated decidual macrophages and increases in activated decidual CD4+ T cells, leading to the secretion of IL-4, a cytokine critical for successful pregnancy, from CD4+ T cells. Interestingly, upregulated HLA-G on human breast cancer cells may interact with LILRB1-expressing CD68+ cells and CD8+ cells to aid infiltration into breast cancer tissues, contributing to tumor development. In contrast, HLA-G homodimer binds LILRB1 on CD14+ macrophages and induces cytokine secretion; in this scenario, LILRB1 acts as an activating receptor.

DCs. The level of LILRB1 decreases following DC activation by CpG-DNA and inflammatory stimuli. Both upregulation and downregulation of LILRB1 are observed during the differentiation from monocyte precursors to DCs. Continuous ligation of LILRB1 during DC differentiation confers a distinctive cell phenotype profile, decreases the susceptibility to CD95-mediated cell death, and inhibits cytokine secretion and the immunostimulatory function of DCs. In immature human monocyte-derived DCs, crosslinking of LILRB1 inhibits osteoclast-associated receptor-mediated intracellular Ca2+ mobilization, cytokine production, T cell proliferation, and resistance to survival factor deprivation. Trophoblast HLA-G may down-regulate allogeneic T cell proliferation by binding with antigen-presenting cells. Urenda et al. observed that the levels of circulating plasmacytoid DCs (pDCs) are correlated with disease activity in systemic lupus erythematosus (SLE) patients and that the expression of LILRB1 is diminished in both pDCs and myeloid DCs (mDCs) from these patients, suggesting that lack of LILRB1 may underlie the defective immune-regulation in SLE patients. HIV-1-infected elite controllers (who maintain undetectable HIV-1 replication in the absence of antiviral therapy) exhibit strong and selective upregulation of LILRB1 and LILRB3, which significantly increase the antigen-presentation abilities of circulating mDCs. LILRB1 also mediates cytokine secretion by mDCs. The complex effects of LILRB1 may be partially due to high levels of polymorphism and mutation of its gene.

T cells. Although LILRB1 can only be detected on the surface of a subset of T cells, it is expressed in the cytoplasm of all human T lymphocytes. The expression of LILRB1 is increased on antiviral CD8 T cells during chronic infection. Soluble anti-LILRB1 stimulates, but cross-linked antibody inhibits, proliferation and functions of antigen-specific T cells. LILBR1 plays a negative regulatory effect on the activation of T cells by inhibiting phosphorylation of linker for activation of T cells (LAT) and of ERK1/2. LILRB1 competes with CD8 in binding to HLA class I molecules and modulates the activity of CD8+ T cells. The HLA-G/LILRB1 interaction on myeloid-derived suppressor cells (MDSCs) expands the population of MDSCs, which inhibited the proliferation and functions of T cells. In a transgenic mouse model in which LILRB1 is expressed on T, B, NK, and natural killer T cells, the interaction of LILRB1 and H-2Db, a murine MHC class I molecule, results in impaired development and function of T cells. Tumor-cell-expressed HLA-G interacts with LILRB1 on Vγ9Vδ2 T cells or CD8+ T cells to inhibit cytotoxicity of these T cells. LILRB1 also mediates activation signaling. For example, interaction of cytomegalovirus protein UL18 and LILRB1 on CD8+ T cells causes non-MHC-restricted lysis of virus-infected cells by resting and activated CD8+ T cells and IFN-γ production by T cells.

B cells. Crosslinking of LILRB1 inhibits antigen-induced B cell activation and suppresses antibody production. Interaction between HLA-G and LILRB1 inhibits B cell differentiation, chemotaxis, Ig secretion, and proliferation by G0/G1 arrest through dephosphorylation of AKT, GSK-3β, c-Raf, and Foxo proteins. Apoptotic LILRB1+ B cells may contribute to the overwhelming cytokine release and the impairment of the immune memory of malaria patients.

Osteoclasts. LILRB1, like LILRBs 2–4, is expressed on immature osteoclasts. During osteoclastogenesis, LILRBs are tyrosine phosphorylated and constitutively associate with SHP-1. LILRB1, LILRB3, and LILRB4 inhibit differentiation of osteoclasts.

Cancer development. As summarized above, tumor cell-expressed HLA-G can interact with LILRB1 on various types of immune cells possibly enabling immune evasion. LILRB1 is directly expressed on certain cancer cells, including AML cells (especially in monocytic AML cells), neoplastic B cells (including B cell leukemia, B cell lymphoma, and multiple myeloma cells), T cell leukemia and lymphoma cells, and gastric cancer cells. There is evidence that LILRB1 protects primary cutaneous CD8+ and CD56+ T cell lymphomas from cell death and that its expression on human gastric cancer cells contributes to enhanced tumor growth. In contrast, binding of soluble or nanoparticle-aggregated HLA-G with LILRB1 on neoplastic B cells inhibits cell proliferation. In addition, blocking of LILRB1 on myeloma or lymphoblastic cells in culture using neutralizing antibodies did not affect cell lysis mediated by NK cells. Context-dependent LILRB1 function in cancer biology warrants further investigation.


LILRB2 (also known as CD85D, ILT4, LIR2, and MIR10) contains four extracellular immunoglobulin domains, a transmembrane domain, and three cytoplasmic ITIMs. It is expressed on hematopoietic stem cells, monocytes, macrophages, dendritic cells, basophils in some individuals, decidual macrophages, mast cell progenitors, endothelial cells, and osteoclasts but not on lymphoid cells. LILRB2 binds to multiple types of ligands, notably HLA class I molecules, CD1d, Angptls, myelin inhibitors (including Nogo66, MAG, and OMgp), and β-amyloid. Unlike LILRB1, LILRB2 does not require β2-microglobulin in the complex to bind HLA ligands. Cis interaction between LILRB2 and HLA ligands on the same cell has been reported. We demonstrated that multimeric Angptls are superior to HLA-G in terms of binding and activating LILRB2.

Studies on the function of LILRB2 have shown that this receptor plays a physiological role in several tissues. In hematopoietic lineages, LILRB2 has been associated with down modulation of immune response through various mechanisms. Crosslinking of LILRB2 with FcγR in vitro led to inhibition of FcR-mediated signaling in monocytes and to serotonin release in a LILRB2-transfected basophilic cell line. Upregulation of LILRB2 induced dendritic cell tolerance. Investigations into the role of LILRB2 in HIV have demonstrated that stronger binding between LILRB2 and HLA class I molecules is positively associated with viral replication, suggesting that this interaction leads to a blunted immune response. LILRB2 and LILRB4 are upregulated in antigen-presenting cells in response to Salmonella infection, suggesting a role of these receptors in balancing the inflammatory response in face of bacterial infection. Our lab has shown that LILRB2 contributes to ex vivo expansion of HSCs likely through inhibition of differentiation. LILRB2 is also expressed and activated on immature osteoclasts during osteoclastogenesis. In neurologic tissues, LILRB2 suppresses axonal regeneration via binding to myelin inhibitors and promotes the development of Alzheimer’s disease through interaction with β-amyloid.

LILRB2 plays various roles in cancer biology as well. Expression of LILRB2 has been reported in various cancer cells including AML, especially the monocytic subtype, some chronic lymphoblastic leukemia (CLL), primary ductal and lobular breast cancer, and human non–small cell lung cancer. By contrast, LILRB2 is not expressed by normal lymphoid cells or normal breast tissues. PirB, the mouse ortholog of LILRB2 and LILRB3, is expressed on MLL-AF9 AML cells including AML stem cells. The functional role of LILRB2 is still under investigation, but in lung cancer, LILRB2 supports cancer cell development and survival.


LILRB3 (also called CD85A, ILT5, LIR3, HL9) contains four extracellular immunoglobulin domains, a transmembrane domain, and four cytoplasmic ITIMs. Expression of LILRB3 has been reported on monocytes, monocyte-derived osteoclasts, neutrophils, eosinophils, basophils, osteoclasts, and progenitor mast cells. There is significant polymorphism in the gene encoding LILRB3.

The ligand for LILRB3 is unknown, and relatively little is known about the function of LILRB3. In human basophils, coligation of LILRB3 with FcεRI inhibits Fc receptor-mediated cell activities in vitro. When LILRB3 is coligated with LILRA2 or IgE receptors on basophils, release of histamines, interleukin-4, and cysteinyl leukotrienes is inhibited. LILRB3 is also proposed to be an inhibitor of allergic inflammation and a contributor to uncontrolled immune responses and autoimmunity. Polymorphisms in LILRB3 are linked to graft-versus-host disease in animal models and to the allergic response. As do several other LILRBs, LILRB3 inhibits differentiation of osteoclasts.

Certain myeloid leukemia, B lymphoid leukemia, and myeloma cells express LILRB3. Of note, the observed coexpression of LILRB3 with stem cell marker CD34 and with myeloma marker CD138 suggests a role in cancer development. Indeed, inhibition of LILRB3 expression in human leukemia cell lines blocks cell growth. Antibodies against LILRB3 induce cytotoxicity of LILRB3-expressing cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. LILRB3 thus is a potential target for anticancer therapy.


LILRB4 (also known as CD85K, ILT3, LIR5, HM18) is unique among LILRB family members in that it contains only two extracellular immunoglobulin domains; it also has a transmembrane domain and three ITIMs. Expression of LILRB4 has been reported on dendritic cells, monocytes and macrophages, progenitor mast cells, endothelial cells, and osteoclasts. Interestingly, the gene encoding LILRB4 is one of the most polymorphic of all receptor-encoding genes with at least 15 known single-nucleotide polymorphisms; the significance of this polymorphism is unclear. LILRB4 is conformationally and electrostatically unsuitable for MHC binding, and the ligand for human LILRB4 is unknown.

Monocytes. LILRB4 is expressed on monocytes and can be upregulated by IFNβ and vitamin D3 during central nervous system inflammation. Upon crosslinking of LILRB4 to HLA-DR, SHP-1 is recruited to LILRB4 through the two ITIMs and inhibits tyrosine phosphorylation of downstream cellular signaling, which inhibits Ca2+ mobilization in monocytes. Similarly, coligation of CD11b or FcγRIII with LILRB4 inhibits monocyte activation. Crosslinking of FcγRI with LILRB4 also significantly reduces FcγRI-induced TNFα production and phosphorylation of Lck, Syk, LAT, ERK, and c-Cbl via recruitment of phosphatases other than SHP-1.

DCs and T cells. Literature showed that LILRB4 from other cell types was capable of inhibiting activation of T cells, on which an unknown ligand for LILRB4 may be expressed. DCs that express high levels of LILRB4 and LILRB2 promote conversion of alloreactive CD4+CD45RO+CD25+ T cells to regulatory T cells (Treg). Both membrane-bound and soluble LILRB4 inhibit T cell proliferation and induce differentiation of CD8+ T suppressor cells (Ts) in vitro and in vivo. Injection of soluble LILRB4 protects allogeneic human pancreatic islet transplantation and prevents graft-versus-host disease via induction of Ts cells. Secretion of cytokines, such as IL-1α, IL-1β, IL-6, IFN-γ, and IL-17A, from DCs, and the transcriptional factor BCL6 are important for Ts induction by LILRB4. On the other hand, LILRB4 expression in Treg cells can be negatively regulated by casein kinase 2, and LILRB4+ Treg cells show attenuated T cell receptor-mediated signaling.

Cancer development. LILRB4 expressed on immune cells may facilitate tumor immune escape. In humanized mouse experiments, both membrane-bound and soluble LILRB4, mainly produced by tumor-associated macrophages, support cancer cell escape from immune suppression through induction of CD8+ T suppressor cells. LILRB4 inhibits T cell proliferation via induction of anergy of CD4+ helper T cells and differentiation of T suppressor cells, suggesting that a ligand or counter-receptor for LILRB4 is expressed on T cells. LILRB4 is also expressed on MDSCs in human lung cancer patients, and shorter survival of patients is associated with elevated MDSC numbers and higher LILRB4 expression.

LILRB4 is also expressed on surfaces of several types of cancer cells. Dobrowolska et al. found that LILRB4 is expressed in all M4 and M5 monocytic AML cells and that it is coexpressed with leukemia stem cell markers CD34 and CD117 in 39% and 50% cases, respectively. Although LILRB4 is not expressed by normal B cells, it was detected in 23 out of 47 patients with chronic lymphoblastic leukemia (CLL) cells with more lymphoid tissue involvement; LILRB4 levels may thus be able to predict the prognosis of CLL. In solid tumors, Zhang et al. found that LILRB4 is moderately expressed in some gastric cancer cells and tissues; together with LILRB1, it may inhibit NK cell-mediated cytotoxicity to gastric cancer cells. More than 40% of patients with certain solid organ tumors such as colorectal carcinoma, pancreatic carcinoma, and melanoma have soluble LILRB4 that can inhibit T cell immunity in vitro. The supportive role of LILRB4 in solid cancers was evidenced by restoration of T cell responses upon treatment with anti-LILRB4 or by depletion of LILRB4 in serum. An animal model of spontaneous ovarian cancer also showed that increased LILRB4 expression is associated with tumor development and progression.


Expression of LILRB5 (also known as CD85C and LIR8) has been reported in subpopulations of monocytes, NK cells, and mast cell granules. A very recent study showed that LILRB5 specifically binds to HLA-B7 and HLA-B27 heavy chains. Due to relative paucity of studies on LILRB5, the functional role of this receptor is not clear. One study suggested that LILRB5 present in the mononuclear phagocytic system of liver might play a role in the clearance of creatine kinase. Within human mast cells, LILRB5 is expressed in cytoplasmic granules that are released after crosslinking of high-affinity IgE receptors, which hints at a possible role in mast cell inflammatory response. LILRB5 is unique among LILRBs in that it is the only LILRB that is not highly expressed by M5 AML cells, and its expression level does not correlate with the overall survival of AML patients based on analysis of TCGA database of AML patients (https://tcga-data.nci.nih.gov/tcga/).


PirB is the mouse ortholog of LILRB2/3; it contains three functional ITIMs. It is expressed on many hematopoietic cells, such as HSCs, DCs, macrophages, neutrophils and eosinophils, B cells, and osteoclasts. Its ligands include MHCI and Angptls, and PirB can interact in cis with MHCI expressed on the same cell. PirB regulates cell activity via direct recruitment of tyrosine phosphatases SHP-1 and SHP-2 for downstream signaling. Along with the well-documented activity of PirB in regulation of hematopoietic cells, there are also studies that show that PirB influences neuron and osteoclast activities and leukemia development in AML.

DCs. Within DCs, the roles of PirB have been relatively well studied with effects including regulating cytokine-mediated signaling, inducing peripheral tolerance within the graft-versus-host disease context, and facilitating DC maturation. PirB suppresses type I interferon secretion in plasmacytoid DCs. When PirB is ectopically expressed in DCs, there is a significant decrease in morbidity and mortality within an allograft graft-versus-host disease model with the DCs exerting a suppressive function on alloreactive T cells. In apparent contradiction, the knockout of PirB was found to impair the maturation of DCs with a hypothesized alteration of cell signaling involving granulocyte-macrophage colony stimulating factor.

Macrophages. The roles of PirB on macrophages appear to be diverse and depend on organs. In the hematopoietic system, differentiation of macrophage precursors and MDSCs is regulated by PirB expression. The deficiency of PirB in MDSCs biases differentiation towards M1 macrophages, which significantly stifles tumor growth and prevents metastasis in an LL2 tumor model. PirB inhibits the activity of intestinal macrophages to prevent the progression of inflammatory diseases such as Crohn’s disease and ulcerative colitis; the knockout of PirB leads to an increased susceptibility to induced colitis. PirB is also a negative regulator in alveolar macrophages and suppresses IL-4 induction of pulmonary fibrosis.

Other hematopoietic cells. PirB is highly expressed in eosinophils with an unexpected contribution to both inhibitory and activating pathways. PirB reduces eotaxin-induced chemotaxis yet promotes chemotaxis response to chitin-induced inflammation. Increased PirB expression results upon differentiation of myeloid lineage cells and B cells. PirB is also expressed on mouse HSCs and binds with Angptls to support ex vivo expansion of adults HSCs. PirB is generally not expressed on mature T cells, but its ectopic expression in peripheral T cells contributes to the suppression of type 1 helper T cell immune response. The exclusion of PirB from mature T cells might allow prompt immune responses.

Osteoclasts. The deletion of PirB in prefusion osteoclasts led to an accelerated rate of osteoclast formation in vitro, and the study authors concluded that PirB negatively regulates osteoclast development. However, PirB-deficient mice show no signs of osteoporosis in models, possibly resulting from involvements of other factors.

Neurons. PirB regulates neural plasticity in the visual cortex. It appears to act as a negative regulator in the nervous system. It stabilizes neuronal networks by minimizing structural changes, which correlates with the slower learning rates with age. Blocking activity of PirB in cortical pyramidal neurons led to enhanced ocular dominance plasticity. The deletion of PirB in a mouse stroke model resulted in more rapid recovery.

Cancer development. PirB supports the development of AML in mouse models by maintaining self-renewal and inhibiting differentiation of these cancer cells. In addition, PirB on MDSCs suppresses differentiation of myeloid-derived suppressor cell into M1 macrophages, which in turn inhibits regulatory T cell activities and tumor development.


gp49B1, or mouse LILRB4, is expressed on macrophages, mast cells, neutrophils, NK cells, and T cells. It contains two extracellular Ig-like domains and two cytoplasmic ITIMs. Integrin αvβ3 is the only known ligand of gp49B1. The ITIMs of gp49B1 interact with SHIP, SHP-1, and SHP-2, and recruitment of SHP-1 to gp49B1 leads to inhibition of mast cell activation. Co-ligation of gp49B1 and FcγRI blocked IgE-mediated mast cell activation. Interaction of gp49B1 with integrin αvβ3 also inhibits mast cell activation and CD40-mediated antibody production by memory and marginal zone B cells. The gp49b-deficient mice exhibit no development abnormality but show hypersensitivity of mast cells to ovalbumin-challenged anaphylaxis, a great elevation of SCF-induced mast cell activation, and increased neutrophil-dependent vascular injury induced by LPS. The activation of mast cells and neutrophil infiltration in gp49b-deficient mice causes parallel increases in secretion of cytokines, such as IL-1β, MIP-1α, and MIP-2, upon type-II collagen antibody and LPS treatment. Moreover, the combination of ovalbumin challenge with LPS sensitization induces gp49B1 expression on DCs. gp49B1 deficiency induces significant T helper cell type 2 immune response and pulmonary inflammation, resulting from elevated chemokine (C-C motif) receptor 7 (CCR7) on gp49B1-deficient DCs and increased secretion of CCL21 by lung lymphatic vessels.


Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1–5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit protein tyrosine phosphatase nonreceptor type 6 (PTPN6 or SHP-1), protein tyrosine phosphatase nonreceptor type 11 (PTPN11 or SHP-2), or Src homology 2 domain-containing inositol phosphatase (SHIP), leading to negative regulation of immune cell activation. Certain of these receptors also play regulatory roles in neuronal activity and osteoclast development. The activation of LILRBs on immune cells by their ligands may contribute to immune evasion by tumors. Recent studies found that several members of LILRB family are expressed by tumor cells, notably hematopoietic cancer cells, and may directly regulate cancer development and relapse as well as the activity of cancer stem cells. LILRBs thus have dual concordant roles in tumor biology – as immune checkpoint molecules and as tumor-sustaining factors. Importantly, the study of knockout mice indicated that LILRBs do not affect hematopoiesis and normal development. LILRBs may represent ideal targets for treatment of cancer and autoimmune disorders.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.UT Southwestern Medical CenterDallasUSA