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 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts 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 receptor 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 gene (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 proteins, 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 paired receptors 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 immune system, 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 chromosome 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 genes for six inhibitory receptors, four stimulatory receptors, certain degree hindered by the divergence of the human and one secreted receptor, and two pseudogenes. 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 phosphatase. 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 ligand. 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 alternative splicing. 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).