The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors Deborah N. Burshtyn and Chris Morcos This information is current as J Immunol 2016; 196:947-955; ; of September 29, 2021. doi: 10.4049/jimmunol.1501937 http://www.jimmunol.org/content/196/3/947 Downloaded from References This article cites 71 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/196/3/947.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors Deborah N. Burshtyn and Chris Morcos The human leukocyte Ig-like family is part of inhibitory receptors with five human and only a single mouse. the paired receptor system. The receptors are widely In contrast, both species encode many activating receptors, and expressed by various immune cells, and new functions more is known about the binding characteristics for the human. continue to emerge. Understanding the range of func- LILR orthologs are found in most mammalian species studied, tions of the receptors is of general interest because sev- and highly related receptor families are found in marsupials, eral types of pathogens exploit the receptors and genetic with more distantly related receptor systems found in birds, diversity of the receptors has been linked to various au- frogs, and perhaps even fish in terms of their Ig domain toimmune diseases. Class I major histocompatibility structure, suggesting that they have arisen from a common Downloaded from molecules were the first ligands appreciated for these re- ancestral (4, 5). In the case of bats, one major lineage lacks ceptors, but the types of ligands identified over the last the family altogether, whereas the other has it greatly expanded several years are quite diverse, including intact patho- (6). Although the evolutionary plasticity in the receptor family among even closely related species makes it tempting to spec- gens, immune-modulatory , and molecules ulate that the expansion and contraction of the family coincides normally found within the CNS. This review focuses with emergence and/or extinction of pathogens, the growing http://www.jimmunol.org/ on the types of ligands described to date, how the in- list of endogenous ligands suggests the selective pressures go dividual receptors bind to several distinct types of li- well beyond the direct interaction with MHC-I and evasion gands, and the known functional consequences of those strategies of pathogens. interactions. The Journal of Immunology, 2016, 196: This review will focus on the newly identified and growing 947–955. list of LILR ligands that are not MHC-I–related along with discussion of the specifics of the LILR interaction with diverse types of MHC-I molecules. Over six distinct ligands have he human leukocyte Ig-like receptor (LILR) family been reported for two of the receptors, and several ligands by guest on September 29, 2021 belongs to the superfamily of that engage multiple receptors (Fig. 1, Table I). The list includes T contain receptors with the potential to transmit stim- endogenous molecules involved in development and responses ulatory or inhibitory signals. In general, these receptors reg- of the , tissue-specific molecules that can be ulate the immune system to temper or augment responses autoantigens as well as binding to intact bacteria, and a by other cells and mark tolerogenic APCs. Paired receptors are member of the flaviviridae. The complex assortment of li- sets of receptors with highly similar extracellular domains gands raises many questions about the functions of the LILR linked to either activating or inhibitory signaling systems. In receptors in various cell types and contexts, how the indi- many cases, the activating receptors share the same ligands as vidual receptors can accommodate binding to the range of their inhibitory counterpart, but the interactions are weaker. ligands, and how these ligands collaborate or cross-regulate The LILR receptors were identified as receptors related to the each other. MHC class I (MHC-I)–specific killer cell Ig-like receptors (KIRs) and one as the receptor to a viral MHC-I mimic General features of LILR (1–3). Despite their identification ∼20 years ago, under- The human LILRs are encoded at 19q13.4 standing of the specific functions of each different receptor within the leukocyte receptor complex. The locus encodes and elucidating their ligands has been relatively slow and to a for six inhibitory receptors, four stimulatory receptors, certain degree hindered by the divergence of the human and one secreted receptor, and two . There is con- mouse receptor family. The difference is most pronounced siderable polymorphism, and copy-number variation likely in the number and probable subfunctionalization of the also contributes to diversity within the population (7–11).

Department of Medical Microbiology and Immunology, University of Alberta, Edmon- Abbreviations used in this article: BST2, bone marrow stromal Ag 2; KIR, killer cell ton, Alberta T6G 2E1, Canada; and Li Ka Shing Institute of Virology, University of Ig-like receptor; LILR, leukocyte Ig-like receptor; b2m, b2-microglobulin; MAG, Alberta, Edmonton, Alberta T6G 2E1, Canada myelin-associated glycoprotein; MHC-I, MHC class I; OMgp, oligodendrocyte my- elin glycoprotein; PIRB, paired Ig-like receptor B; SHP, Src homology region 2 Received for publication September 1, 2015. Accepted for publication October 27, domain–containing . 2015. This work is supported by Canadian Institutes for Health Research Grant MOP 123257 Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 (to D.N.B.). Address correspondence and reprint requests to Dr. Deborah N. Burshtyn, Department of Medical Microbiology and Immunology, 6-020 Katz, University of Alberta, Edmon- ton, AB T6G 2E1, Canada. E-mail address: [email protected]

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501937 948 BRIEF REVIEWS: LILR LIGANDS Downloaded from http://www.jimmunol.org/

FIGURE 1. LILR interactions. The known LILR interactions are illustrated for the receptors depicted on a generic APC interacting with cell-surface and soluble ligands. The shaded LILR domains indicate those domains have been mapped as important for the interaction with the . The dashed lines of the MHC-I free H-chains (FHC) and B27 indicate their altered a1 and a2 conformation compared with the full complex. The receptor labels lack the LILR for clarity of the figure. The receptors that lack known ligands are illustrated for completeness. DC, dendritic cell; LTA, lipoteichoic acid. by guest on September 29, 2021 Monocytes express all but one of the receptors, whereas most structural relationship to one another, and they likely use immune cell types express at least one member of the LILR distinct surfaces to engage the array of distinct ligands. family (Table I). In general, what distinguishes the inhibitory and stimulatory forms of the receptors is the presence of Interaction with native classical MHC-I ITIMs in the cytoplasmic tail of the inhibitory receptors or a To date, five LILRs have been shown to bind to classical MHC- positively charged arginine in the transmembrane region of I proteins. LILRB1, LILRB2, and LILRA3 bind a spectrum of the activating receptor that couples the receptor to the ITAM- classical class I alleles. The interaction between LILRB1 and containing adaptor FcRg. The inhibitory forms are denoted LILRB2 and classical MHC-I proteins has been well charac- by “B” in the name and numbered to identify the various terized through structural studies (13–16). Both these recep- receptors, whereas the activating forms are denoted with “A.” tors have four Ig domains and use the two membrane distal The receptors typically have four Ig domains, a stem region, domains (D1 and D2) to contact conserved features of the transmembrane domain, and a cytoplasmic tail. The excep- a3-domain and b2-microglobulin subunit of the MHC-I tions are LILRB4 and LILRA5, which only have two Ig do- proteins. The interaction with these highly conserved re- mains, and LILRA1, for which a two-domain isoform is gions of the MHC-I explains how both receptors bind the created by . LILRA3 is the sole secreted range of MHC-I subtypes and alleles, but there are details of form, and even though it has an A in its name, it cannot the interaction that differ between the two receptors. Specif- directly transmit an activating signal. In contrast, paired Ig- ically, LILRB2 has a larger interaction interface with the a3 like receptor B (PIRB), the single inhibitory receptor in domain, whereas LILRB1 is highly dependent on the interac- mouse, has six Ig domains. How the PIRB domains relate to tion with b2-microglobulin (b2m) to form a stable complex. the various LILRB domains will be discussed further below. Why there are two LILRs with such similar binding capa- The human LILR receptors are divided into two groups bilities for MHC-I is not clear, but perhaps is related to based on their sequence similarity relative to MHC-I binding differential expression by cell types or the variety of non– (12). As will be covered in the following section, the first MHC-I ligands that the two receptors have evolved that are group has high similarity with each other within the MHC-I distinct that will be covered in subsequent sections. Although binding regions, and, although most do, they have not all the LILRB1 and LILRB2 both bind to all HLA-A, -B, and -C been shown to bind to MHC-I. The remaining receptors tested, sequence differences of the MHC-I molecules do im- differ from the group 1 at the MHC-I contact region and pact the strength of the binding. Jones et al. (17) performed share certain residues at these locations with each other (12); the most comprehensive comparative assessment examining however, their ligands identified to date bear little obvious the interaction of two receptors with .90 alleles of MHC-I The Journal of Immunology 949

Table I. Summary of LILR family ligands

Receptor No. of Ig Domains Expression Ligands LILRB1 4 Mo, Mac HLA-A, -B, -C, -F, and -G DC HLA-B27 H-chain dimer? HSC CMV UL18 B S100A9 NK-subset S. aureus and E. coli T-subset Dengue virus LILRB2 4 Mo, Mac HLA-A, -B, -C, -F, and -G DC HLA-B27 H-chain dimer? HSC CD1d and CD1c Neuron? HLA-B27 H-chain dimer MAG, Nogo66, OMgp Angiopoietin-like 2 and 5 Ab42 LILRB3 4 Mo, DC, Gran S. aureus Angiopoietin-like protein 2 and 5 LILRB4 2 Mo, Mac, DC, ? plasmablast

LILRB5 4 Mo, Mac HLA-B7 Downloaded from HLA-B27 H-chain dimer Angiopoietin-like protein 2 and 5 LILRA1 4 or 2 Mo, Mac HLA-B27 DC HLA-B27 H-chain dimer HLA-C free H-chain LILRA2 4 Mo, Mac, ?

DC, Gran, http://www.jimmunol.org/ T, NK LILRA3 4 Mo, Mac, DC, HLA-C.HLA-A, HLA-G B, T-Subset LILRA4 4 pDC BSA2 LILRA5 2 MO, PMN ? LILRA6 4 Mo ? DC, dendritic cell; Gran, granulocyte; HSC, hematopoietic stem cell; Mac, macrophage; Mo, monocyte; pDC, plasmacytoid dendritic cell; PMN, polymorphonuclear neutrophil. by guest on September 29, 2021 using Luminex technology. Their study indicates a polymor- tissue, such as placenta that expresses HLA-C, but not -A or phism in the a3 domain influences LILRB1 binding (17). -B (reviewed in Ref. 21) or the ability to respond in scenarios The change involves a proline at position 193 that is in tight in which HLAs are differentially manipulated by a virus such linkage disequilibrium with an isoleucine/valine dimorphism as HIV (reviewed in Ref. 22). There are no studies indicating at position 194, a residue that makes direct contact with a functional interaction of LILRA1 with MHC-I with cells LILRB1 (14). In contrast, LILRB2 binds A . B . C and naturally expressing LILRA1, but it would be expected to only weakly binds a few of HLA-B alleles, including the counterbalance LILRB1 and -B2 signals in cells that coexpress disease-associated HLA-B*2705 (17). In contrast to the re- the receptors, such as monocytes/macrophages and dendritic gions that influence LILRB1, MHC-I polymorphisms that cells. LILRA3 is constitutively expressed by monocytes at low influence LILRB2 binding are restricted to the MHC-I a1 levels and upregulated in response to inflammatory states and domain. Insensitivity to the a3 domain polymorphisms likely in response to IL-10 in vitro (23) as detected in serum, sug- relates to the differences in how the LILRB2 interacts with the gesting it might provide feedback control on inflammatory a3 with a more extensive interface that can accommodate the responses. Purified LILRA3 can suppress TNF-a production changes in b2m. However, an interaction by the D3D4 do- by LPS-stimulated PBMC, implying a regulatory role (24). mains could explain the LILRB2 sensitivity to differences in However, the latter study did not determine if MHC-I was a1. Such an interaction was proposed by Nam et al. (18), who the necessary ligand in this context. In fact, Lee et al. (24) solved the structure of the two membrane proximal domains showed preferential binding to monocytes over other lym- independent of the rest of the receptor. These authors suggested phoid cells that have high levels of MHC-I, suggesting thattheD3D4domainscouldwrapoverthetopofthea1a2 LILRA3 has another ligand and also that the binding to domains of the class I in a manner reminiscent of the KIR3DL1– monocytes requires native glycosylated LILRA3. LILRB3, MHC-I interaction (19), but there is no known influence of LILRB4, and LILRA5 appear not to bind MHC-I, as they peptide on the interaction of LILRs with MHC-I. have been tested using assays with soluble receptors and class I The remaining group 1 LILRs are LILRA1, LILRA2, and on cells and/or surface plasmon resonance (16, 25, 26). LILRA3. LILRA1 and LILRA3 also broadly bind classical MHC-I, and, as is characteristic of paired receptors, the in- Nonconventional MHC-I ligands teraction is of lower affinity than that of the inhibitory re- A few of the LILRs interact with classical class I molecules in ceptors (17, 20). Curiously, these receptors also bind HLA-C a more allele-specific manner than LILRB1 and LILBR2 or better than HLA-A and -B, which is opposite to LILRB2. The prefer the semidenatured free H-chains. LILRA1 and LILRA3 preference for HLA-C could indicate function in a specialized share preferential binding to HLA-C (17), but the significance 950 BRIEF REVIEWS: LILR LIGANDS of the specificity is not obvious, although, as mentioned LILRB1 and LILRB2 both interact with HLA-G (36). HLA- above, it could be important to stimulate responses to path- G expression is normally found on placental trophoblasts ogens that downmodulate HLA-A and -B and not -C. butitisalsoexpressedbyavarietyofcancers.LILRB1and LILRB5 interacts specifically with B7 and B27, but the mo- LILRB2 are expressed on cell types that are important during lecular basis for the specificity remains unclear. Given the placentation such as NK cells and monocytes, suggesting the HLA-Bw4–specific KIR3DL1 is likely representative of the interaction of HLA-G and the LILRs could be highly selected ancestral KIR, defining how LILRB5 is HLA-B specific might for in humans (21). The affinity of LILRB1 and LILRB2 for also provide insight into the evolution of the subtype speci- HLA-G is above that for classical MHC-I, suggesting HLA-G ficity of the KIRs (27). Several of the LILRs are able to in- might be a more potent ligand, and better functional recog- teract with the H-chain of the MHC-I in the absence of b2m. nition of HLA-G relative to classical MHC-I has been shown This conformation of the MHC-I is known as the free H- using NK cells that express LILRB1 (35–37). The ability of chain or open conformer, as the peptide is rapidly lost from HLA-G to form dimers further enhances the binding. There the free H-chain as well, and the conformation of the a1-a2 remain many questions regarding when HLA-G acts through domains is altered, precluding most Abs from detecting the LILRs, including during tumor progression in which devia- species. Specifically, LILRB2, LILRA1, and LILRA3 bind to tion of the inflammatory response by macrophages is pivotal. acid denatured HLA molecules, and this can be blocked by HLA-F is one of the least well understood of the nonclassical Ab to the free H-chain. Interestingly, although both LILRB1 MHC-I proteins. LILRB1 and LILRB2 can bind to HLA-F and LILRB2 have been shown to bind to different HLA-B27 (38). However, as HLA-F remains largely intracellular in Downloaded from subtypes, only LILRB2 measurably binds the H-chain form normal conditions (38), the physiologic consequence of the of HLA-B27 (28). Moreover, LILRB2 preferentially binds binding by the LILRs is unclear. It is worth noting that HLA- dimers of HLA-B27 (29). One can only speculate about G and HLA-F are thought to be more recent additions to the when free H-chain forms of MHC-I are biologically active, class I–like than HLA-E (39). In relation to this, when di- but they are known to increase on activated T cells (30) and rectly tested, no binding of LILRB1 can be detected to HLA- disulphide-linked dimers of the B27 H-chain occur at steady E (40, 41). It is curious that these receptors do not bind HLA- http://www.jimmunol.org/ state (31). The structure of MHC-I H-chain only dimers are E because the a3 domain is so highly conserved (as illustrated also unclear, but there are global differences in the fold, and in Ref. 30) (36). To our knowledge, binding to the HLA-E likely the dimer alters accessibility to the a3 domain. The and HLA-G has not been tested for other types of LILRs, but strong association between HLA-B27 and spondyloarthropathies given the conservation of the a3 domain, it is likely to follow inspired models of how the interaction between misfolded soluble the same pattern as for the classical molecules. HLA-B27 and LILRB2 could trigger inflammation (32). Alter- CD1. LILRB2 interacts with CD1d and CD1c, class I–like natively, because the activating LILRA1 also interacts with B27, it proteins that are more divergent than HLA-F or -G from the

might be involved in promoting responses. classical class I forms (42, 43). CD1 molecules associate with by guest on September 29, 2021 Although LILR interactions with classical class I has been b2m and are involved in Ag presentation to specialized extensively examined in terms of class I variation, the reciprocal NKT cells. Li et al. (42, 43) have shown that the contact site examining diversity of LILRs binding to MHC-I has only been between LILRB2 and CD1d involves the two membrane tested in one case in which a link between polymorphism in distal Ig domains of LILRB2 and the Ag-binding domains LILRB1 and rheumatoid arthritis showed that alterations in of CD1d and can occur in cis. The interaction blocks expression levels and not binding were involved (25). How- the loading of lipid Ags onto CD1d and inhibits NKT ever, LILR genetic diversity and/or altered expression is quite activation. CD1c upregulation can apparently inhibit the possibly involved with autoimmune disease or changes in the regulatory effects of the LILRB2–CD1d interaction on Ag response to infection, and this has been reviewed elsewhere presentation by titrating away the LILRB2 (42, 43). There recently (33). is some specificity on the side of the LILRs, as LILRB1 does Another interesting feature of the LILRB1 and LILRB2 is not recognize CD1c or CD1d, but to our knowledge, other the ability to interact in cis with MHC-I proteins, and the cis- LILRs nor the mouse counterpart PIRB have not been tested interaction may provide tonic signals or regulate the avail- in this regard. The studies published to date did not assess if ability of the receptor for interaction in trans and/or regulate LILRB2 interacts with CD1 in trans, and it is not clear accessibility to ligands in trans (34). Although it is hard to when a trans interaction would occur naturally. The different imagine the molecular rearrangement, the cis-interaction appears expression patterns of the CD1 molecules could mean that to use the same regions of the receptor and ligand, at least in LILRB2 regulates the CD1 pathway in cells such as dendritic terms of the ability of Abs to disrupt the cis-interaction (35). cells that express LILRB2, but not typical B cells that express LILRB1. Perhaps B cells that are involved in lipid Ag presentation Nonclassical MHC-I ligands to NKT cells (44) use LILRB2 to regulate their function. The idea Nonclassical MHC-I proteins provide distinct functions from that LILRB2 binds to CD1 is remarkable because CD1 is an classical MHC-I and generally do not present Ag to con- ancestral MHC-like molecule (39), and the interaction with the ventional T cells. The nonclassical MHC-I proteins often play LILR family could predate the evolution of interactions with important roles in cross-talk between particular subsets of classical MHC-I, forcing the receptor to find the conserved immune cells, and their expression can be either tissue or cell regions of b2m and the a3 domain. type restricted and tightly regulated. The nonclassical MHC-I proteins are potentially very important ligands of LILR in Pathogen-derived ligands particular contexts, and interactions have been described with UL18. LILRB1 was first identified as the receptor for the LILRB1 and LILRB2. MHC-I mimic in human CMV (1). The interaction with the The Journal of Immunology 951 viral molecule is similar to the interaction with the endogenous and Listeria monocytogenes were tested but do not interact (50). A MHC-I, except that the interface is much larger with more follow-up study with mutant strains of S. aureus implicates extensive contacts, which explains the 1000-fold higher affinity lipoteichoic acid as important for the interaction of S. aureus with UL18 (15, 45). The ability of UL18 to inhibit NK cells with PIRB, but as there is no interaction with other bacteria has been documented, suggesting that the primary function of that have lipoteichoic acid in their cell wall, lipoteichoic acid is UL18 is to subvert the NK response (46). However, LILRB1 is not sufficient (51). Further studies are required to determine if expressed on a range of cells that are involved during the response lipoteichoic acid is the moiety involved in LILRB1 and B3 to CMV such as T cells, and there it has been shown in one binding bacteria as well. Although the functional consequences report to costimulate the T cells by a yet-undefined signaling of the bacteria binding to human LILRs in vivo remains unclear, mechanism and may also stimulate NK cells that lack LILRB1 the physiologic consequence of the PIRB–S. aureus interaction in (46, 47). Another possibility is that UL18 could impact virus mice suggests engaging PIRB provides immune evasion for replication through a cis-interaction with LILRB1 within cells bacteria, as PIRB-deficient mice have enhanced clearance of in which the virus replicates that also express LILRB1, such as S. aureus. The situation with S. aureus is in contrast to an monocytes. Although it is not possible to directly test the function earlier report of an enhanced susceptibility to Salmonella in of UL18 on CMV pathogenesis in humans, it might be useful PIRB-deficient mice, which is thought to be a defect in control to determine if mouse PIRB binds any of the MHC-I–like of replication within macrophages (52). Whether or not PIRB proteins of mouse CMV that have conservation with the a3- can bind Salmonella is not known, and it is also possible that the domain of mouse MHC-I. situation varies for bacteria such as Salmonella that replicate Downloaded from Dengue virus. Dengue virus is a second virus reported to exploit inside cells that express PIRB. In addition, prevention of LILRB1 during infection, but in this case, it is through an lipoteichoic acid formation for the cell wall enhances bacterial interaction with the intact virus. The discovery was made virulence, perhaps suggesting a role for the stimulatory PIRA1 through screening derivatives of a monocyte cell line with interaction as important to contain the infection in addition to altered susceptibility for Ab-mediated infection (48). Dengue other pattern recognition receptors known to sense lipoteichoic virus is a major pathogen that causes serious illness in subsets acid. Therefore, future studies should address defining the http://www.jimmunol.org/ of patients, and severe forms of dengue infection are as- structure that the LILRs and PIRs interact with to explain the sociated with new infection in the face of pre-existing Ab specificity for bacterial species and whether there is benefit to to related strains that facilitate infection of monocytes. Ab- disrupting the interactions for treatment of sepsis. One important mediated infection of monocytes is enhanced by simultaneous point relevant to how these interactions could be targeted is that interaction of Ab-coated virus with FcRs and LILRB1 (48). MHC-I was not competing for the interaction with S. aureus, The interaction between LILRB1 and dengue virus on monocytes suggesting interactions with MHC-I in cis or trans are not downregulates expression of IFN-stimulated genes that would regulating the interaction.

otherwise limit virus replication. The mechanism involves by guest on September 29, 2021 counteracting the FcgR signaling through Src homology region Host immunomodulatory proteins 2 domain–containing phosphatase (SHP)-1 recruitment to Bone marrow stromal Ag 2 (BST2) was the first endogenous LILRB1 (48). Although the molecular details of the receptor non–MHC-I–related ligand identified for an LILR family interaction with dengue virus have not been elucidated, dengue member and the first ligand defined for a family member that is a rather simple virus with only two surface proteins, E and is activating (53). As its name suggests, BST2 is expressed on M, and LILRB1 interacts with isolated E protein, although the bone marrow stromal cells, but it is also on plasma cells and interaction with the entire virus is stronger (48). Although there induced by type I IFN on a variety of cells. BST2 also goes by appears to not be a strong association of LILRB1 genotype in the name for its ability to prevent release of a wide dengue shock syndrome (49), it is still possible that variation range of enveloped viruses, although many viruses have of LILRB1 in the population might relate to susceptibility to methods to circumvent it (reviewed in Ref. 54). BST2 binds dengue infection. It also remains to be seen if dengue interacts LILRA4, which is expressed on monocytes, immature den- with other LILRs, as only LILRB4 was ruled out by the initial dritic cells, plasmacytoid dendritic cells, and plasmablasts. report, or if other related flaviviruses also target LILRs. Counterintuitively for an activating receptor, LILRA4 inter- Bacteria. LILRs were reported as receptors that can interact action with BST2 decreases TLR7/9-mediated production directly with bacteria in a study that was designed to identify of type I IFN and other proinflammatory mediators (53). receptors that facilitate adherence of Staphylococcus aureus to However, DAP-12–coupled receptors also limit the TLR re- cells (50). The impetus for the study was the finding that sponses, and DAP12 signals through the same pathway as the S. aureus triggers responses through TLR2 indirectly, and LILRA4-associated FcRg chain (55). The molecular details of therefore, the search was actually for molecules that would the physical interaction between LILRA4 and BST2 remain to allow bacteria to bind to the cells. In addition to binding be resolved, and BST2 has no obvious relationship to other S. aureus, LILRB1 and PIRB bind , and LILRB3 LILR ligands except an overall coiled-coil structure seen in the also binds S. aureus, whereas PIRB also binds Helicobacter envelope protein of dengue virus. BST2 is composed of a pylori. Only one of the activating PIRs tested bound signifi- coiled-coil dimer that loops out from the membrane and is cantly, indicating there is specificity in terms of the receptors localized to lipid rafts by a GPI anchorage at the C terminus. that can interact with these bacteria, although to our knowl- Clarification of how LILRA4 binds to BST2 will be required edge, binding by other members of the LILR family was not to predict if this function is conserved in any other species and tested. There is also specificity of the interaction in terms of may provide insight into putative ligands of the related LILRs. the type of bacteria that does not align with being Gram- Angiopoietin family. LILRB2 was identified as the receptor for all positive or -negative, as Bacillus subtilis, Pseudomonas aeruginosa, seven angiopoietin-like proteins through an expression-cloning 952 BRIEF REVIEWS: LILR LIGANDS approach to identify receptors for these orphan secreted proteins receptor ligands, myelin-associated glycoprotein (MAG) and (56). These were the first soluble ligands to be identified for oligodendrocyte myelin glycoprotein (OMgp), and the LILRs, and binding is quite strong, with a binding is very strong, with a nanomolar range dissociation in the nanomolar range for angiopoietin-like protein 5. The constant for MAG (59). PIRB binds all three known Nogo high Kd is in keeping with signaling by a soluble ligand, receptor ligands derived from myelin, Nogo, MAG, and although still not as high as many cytokine or chemokine OMgp, illustrating the conservation of the interaction and interactions. A weaker interaction with LILRB3 and LILRB5 suggesting it is biologically important. Characterization of with angiopoietin-like protein 2 and 5 was also reported, and the functional consequences and details of the interaction the interaction is specific, as several other LILRs tested did not have only been studied for PIRB, and it is unclear what can display detectable binding, although LILRA3, -5, and -6 were be extrapolated to the human system at this point. Nonetheless, not tested. In this case, the details of the binding have been PIRB is expressed on particular neurons, and subsequent studies characterized. The interaction involves the first and fourth Ig by the Shatz group and others (60–63) have shown that PIRB domains of the receptor and maps to short stretches in each regulates axon regeneration in a SHP-dependent manner and with a similar motif GRY/GTY and critical glycine and tyrosine even neural stem cell survival. PIRB has six Ig domains, and, residues (57). The interaction extends to mouse PIRB and can be similar to LILRB2, the first two Ig domains mediate the exploited to promote proliferation and maintenance of human interaction with mouse MHC-I molecules (64). In contrast, and mouse hematopoietic stem cells in mouse models (56, 57). the third to sixth domains mediate the strongest binding

The effect of angiopoietins through LILRB2 illustrates the with Nogo, but the first two alone also interact but with a Downloaded from context-dependent signaling of these receptors because the 10-fold lower dissociation constant (64). Takai et al. (64) binding of the soluble angiopoietins increases phosphorylation used surface plasmon resonance to define binding constants of CAMK-2, a signaling cascade that is important for stem cell with Nogo and PIRB that are submicromolar. Furthermore, maintenance. It is worth noting that defects in hematopoiesis they found that Nogo competes with MHC-I for binding have not been described for PIRB-deficient mice and that to PIRB (64). Interestingly, Takai et al. (64) also found angiopoietin-like proteins are made by a wide range of cell expression of Nogo inhibitor proteins in immune cells outside http://www.jimmunol.org/ types and in response to various stimuli, making it hard to the CNS and that deletion of Nogo impacts the response of mast predict the full physiologic implications of the binding to cells to LPS. The latter observation suggests a cis interaction LILRBs in humans. However, it might be possible to exploit between PIRB and endogenously produced Nogo regulates the pathway for purposes of long-term reconstitution of the TLR signaling. Nogo-B is also expressed by mouse and human immune system (56). endothelial cells, and a recent report shows that endothelial- S100A. One recent study has implicated an interaction of derived Nogo-B is important in downregulating macrophage- LILRB1 with a damage-associated molecular pattern protein, mediated vascular remodeling through PIRB (65). Furthermore,

S100A9. The interaction was found in a study to identify non– PIRA also binds to Nogo, although the binding strength is by guest on September 29, 2021 MHC-I ligands of LILRB1 on HIV-infected dendritic cells, 10-fold less and only detected for the third to sixth domains. because LILRB1 upregulation is associated with enhanced The functional importance of the interaction with PIRA with function in this context (58). The two other known receptors Nogo has not been determined, but some functions of PIRA for S100A9 are TLR4 and receptor for advanced glycation end are known, such as regulating cytokine-driven maturation of products (RAGE), and they are generally thought to promote eosinophils (66), providing some idea of the possibilities. The inflammation. The findings of the interaction between LILRB1 measured interaction with PIRA also begs the question of and S100A9 await confirmation by other studies, as does better which other LILRs might interact with the NogoR ligands as characterization of interaction. However, S100A9 can also well. The difference in domain organization between PIRB and function as a soluble tetramer, and stimulating LILRB1+ NK LILRB2 makes it hard to predict how LILRB2 interacts with cells with exogenous tetrameric S100A9 marginally increases Nogo,MAG,andOMgp,butitismostlikelythattheinteraction TNF-a production and produces some enhanced anti-HIV would compete with MHC-I as well. Whether or not LILRB2 is activity compared with unstimulated NK cells (58). The S100A9 also expressed by human neurons is unclear, but there is protein can be held on the surface of an APC and could regulate expression within the CNS that is likely due at least in part other cells through LILRB1 in that context, too. It is tempting to to immune cells within the CNS such as microglia cells and speculate that LILRs could be important for transducing would also be present on infiltrating monocytes during disease signals from these or other damage-associated molecular states. Moreover, it will be very interesting to determine if the patterns to control inflammation, and further studies with myelin inhibitors of the Nogo pathway are also expressed in other cell types expressing LILRB1 could be informative as human cells outside of the CNS. It is also possible that when well as exploring the possibility that other LILRs bind to the myelin sheath is being destroyed in demyelinating diseases S100A9. such as multiple sclerosis, interactions of LILRB2 on immune cells within the CNS play a regulatory role through this axis. CNS-derived ligands b amyloid. Soluble oligomeric b amyloids are known to damage Nogo receptor inhibitors. The Nogo receptor limits axonal neural synapses and impair synaptic plasticity. Based on earlier growth through interactions with several components of studies that implicated PIRB in regulating synaptic plasticity, myelin, and studies with Nogo receptor–deficient mice indi- Kim et al. (67) tested if PIRB was a receptor for b amyloids cated there are other receptors involved in the process. In a and found that the oligomeric form of b amyloid peptide screen for the additional receptors for Nogo, Atwal et al. (59) Ab42 is a PIRB and LILRB2 ligand. The binding is specific identified LILRB2 using an expression-cloning strategy. They in that there is no detectable interaction with two PIRA receptors also found that LILRB2 binds two additional known Nogo tested, rat PIRB, LILRB1, or LILRB3. The interaction maps to The Journal of Immunology 953 thefirstandsecondIg-likedomainsofbothLILRB2andPIRB, important in the handling of bacteria by innate immune cells, suggesting it would compete with MHC-I as well. PIRB-deficient and one bacteria, Neisseria gonorrhoeae, has exploited a re- mice were spared damage to synaptic plasticity in the mouse ceptor to promote its infection of the genital tract (70). Given Alzheimer model, providing a functional consequence for loss the propensity for genetic diversity within the receptor family, it of PIR-B revealed in a murine Alzheimer model that generates seems likely that some of the diversity will impact the interac- b amyloids (67). In this case, the damage is suggested to be directly tions with the growing list of non–MHC-I ligands. It is also through stimulation of a cofilin-linked pathway in corticol neurons possible that polymorphisms in LILR could alter interaction that express PIRB. Although follow-up studies that confirm with the microbiome and exert an influence on autoimmune LILRB2 is expressed in neurons and not just resident APCs are disease, an area of tremendous general interest of late. The recent required, the study generates an obvious target to protect neurons studies suggest there are many potential areas for therapeutic in such types of neurodegenerative disease. Other questions remain, intervention in infection, such as blocking LILRB1 in dengue such as if any of the LILRs not tested share the specificity for virus–infected patients. amyloid proteins and whether there are functions for the The discovery of PIRB expression in mouse neurons and interaction outside the CNS. NogoR1 inhibitor expression outside the CNS strengthens The discovery by Atwal et al. (59) and Kim et al. (67) of overlap between immune and CNSs, two systems that un- interactions of LILRB2 and PIRB with these different types of derwent parallel diversification in the same evolutionary win- proteins important to the pathophysiology of neurodegener- dow of vertebrate radiation. It will be exciting to determine ative and inflammatory diseases within the CNS is provoca- which LILRs are expressed in human neurons and the affiliated Downloaded from tive. To date, the studies have focused on the role of these developmental and repair processes as well as how their ex- interactions in neurodevelopment and synaptic function as pression in the Ag-presenting and immunomodulatory cells opposed to roles in the immune response. Future studies that within the CNS relates to neuroinflammation. The binding to extend to immune regulation will likely provide very inter- amyloid proteins also tempts speculation that these receptors have esting information. properties of scavenger receptors. PIRB/LILRB2 in CNS appears

to use different downstream effectors in addition to SHP-2 in http://www.jimmunol.org/ Implications and future questions response to b-amyloid, illustrating that the cellular context in- The LILR family continues to emerge as a very complex and fluences the signaling properties of the LILRs. There are a few pleiotropic receptor system. The broad expression of LILRs on examples in which receptors with ITIMs promote inflammatory sentinel cells of the immune system suggest that the individual responses or those with ITAMs limit them, although some of receptors play diverse and specific roles in immune responses in these areas warrant further studies to solidify the results. a context-dependent manner. Although first appreciated for Cancer therapy is another area to be considered in the their interaction with MHC-I proteins, it is becoming obvious context of LILRs. HLA-G expression has emerged as a marker that the importance of the interaction with MHC-I relative to of poor prognosis, and altered LILR expression within a tumor by guest on September 29, 2021 the emerging list of diverse ligands needs to be clarified as context has been reported (reviewed in Ref. 71). There is well as their physiological roles. The newly described func- already a report that LILRB1 can limit the NK-mediated Ab- tions include modulating Ag processing, growth, and differ- dependent cellular cytotoxicity response associated with Ab- entiation. The interplay between soluble immunomodulatory based therapies to treat cancer (72). Therefore, targeting the proteins such as S100A9 or angiopoietin-like proteins and LILR interactions with classical and nonclassical MHC-I ligands that are cell-surface proteins will require further in- proteins may provide another avenue to reprogram the im- vestigation. The potential to interact in cis should also be mune response akin to the successful checkpoint blockade considered in investigating the function of other family mem- strategies employed to restore tumor-specific T cells responses. bers, particularly for those with lower affinity for MHC-I as well as the many disparate ligands. The wide variety of en- Conclusions dogenous non-MHC LILRB2 ligands and the expression pat- In conclusion, the growing list of ligands for the LILR family tern of the receptor raise several questions with regards to its provides much fodder for future investigation, and time will functions and its potential involvement in physiological reveal the extent to which the new information can be exploited processes other than immunomodulation. Given the range for understanding and treating disease. of molecules identified to date of the other members of the family, it should/would be beneficial to cast a wide net in Acknowledgments We thank Drs. Mary Carrington, James Stafford, and Kathy Magor and the searching for the ligands for the members of the family that members of the Burshtyn and Stafford laboratories for many helpful discus- remain without known ligands (Table I). sions and Kang Yu for comments on the manuscript. The interaction of LILRB1 with bacterial pathogens suggests they are under evolutionary pressures from these pathogens, but also suggests additional potential function as receptors that Disclosures The authors have no financial conflicts of interest. assist in monitoring and perhaps internalization of bacteria. This has been observed for parallel receptor families in humans as well as other species such as FcRs and the carcinoembryonic References 1. Cosman, D., N. Fanger, L. Borges, M. Kubin, W. Chin, L. Peterson, and Ag-related cell adhesion molecule family that is targeted by M. L. Hsu. 1997. A novel immunoglobulin superfamily receptor for cellular and bacteria (reviewed in Ref. 68) and even the distantly related viral MHC class I molecules. Immunity 7: 273–282. catfish receptors that mediate (69). In particular, 2. Colonna, M., F. Navarro, T. Bello´n, M. Llano, P. Garcı´a, J. Samaridis, L. Angman, M. Cella, and M. Lo´pez-Botet. 1997. A common inhibitory receptor for major there is a potential parallel with carcinoembryonic Ag-related histocompatibility complex class I molecules on human lymphoid and myelomo- cell adhesion molecules, as these ITIM-bearing receptors are nocytic cells. J. Exp. Med. 186: 1809–1818. 954 BRIEF REVIEWS: LILR LIGANDS

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