The Biology and Disease Relevance of CD300a, an Inhibitory Receptor for Phosphatidylserine and Phosphatidylethanolamine This information is current as of September 30, 2021. Olatz Zenarruzabeitia, Joana Vitallé, Cristina Eguizabal, Venkateswara R. Simhadri and Francisco Borrego J Immunol 2015; 194:5053-5060; ; doi: 10.4049/jimmunol.1500304 http://www.jimmunol.org/content/194/11/5053 Downloaded from References This article cites 85 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/194/11/5053.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 30, 2021 *average 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 © 2015 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 Biology and Disease Relevance of CD300a, an Inhibitory Receptor for Phosphatidylserine and Phosphatidylethanolamine ´ † ‡ Olatz Zenarruzabeitia,*x Joana Vitalle,* Cristina Eguizabal, Venkateswara R. Simhadri, and Francisco Borrego*, The CD300a inhibitory receptor belongs to the the association with adaptor proteins carrying ITAMs or CD300 family of cell surface molecules that regulate a PI3K-binding motif (YxxM) (1, 2). a diverse array of immune cell processes. The inhibi- The human CD300 multigene family has seven members, tory signal of CD300a depends on the phosphorylation which are named alphabetically according to their location of tyrosine residues embedded in ITIMs of the cyto- on chromosome 17. The mouse counterparts, also known as Downloaded from plasmic tail. CD300a is broadly expressed on myeloid CLM, LMIR, and MAIR, are encoded by nine genes located and lymphoid cells, and its expression is differentially on mouse chromosome 11, the syntenic region of human regulated depending on the cell type. The finding that chromosome 17 (4, 5). Nonetheless, with the exception of the CD300a recognizes phosphatidylserine and phosphati- two ITIM-bearing receptors (CD300a and CD300f), the rest dylethanolamine, two aminophospholipids exposed on of the CD300 family members are not perfect functional the outer leaflet of dead and activated cells, has shed orthologs (4, 5). All of the receptors of the CD300 family http://www.jimmunol.org/ have an extracellular IgV-like domain. The activating mem- new light on its role in the modulation of immune bers have a short intracellular tail, and the transmembrane functions and in its participation in the host response domain associates with ITAM-containing adaptor proteins, to several diseases states, such as infectious diseases, such as DAP12 and FceRIg, whereas the inhibitory receptors cancer, allergy, and chronicinflammatorydiseases. have a long intracellular tail that carries ITIMs. In addition to This review summarizes the literature on CD300a ex- the IgV-like domain, CD300g has an extracellular mucin-like pression, regulation, signaling pathways, and ligand domain, but it does not have a known intracellular signaling interaction, as well as its role in fine tuning immune motif (4, 5). It was shown that CD300 family members have cell functions and its clinical relevance. The Journal the potential to form homodimers and heterodimers, which by guest on September 30, 2021 of Immunology, 2015, 194: 5053–5060. implies that, in addition to the signal that emanates from each single receptor, the formation of heterocomplexes adds a new o preserve the identity and integrity of the host and, at layer of intricacy to the signaling pathways of the CD300 family of receptors (6). the same time, be effective against offenses, a complex In this review, we focus on the biology and disease relevance and delicate balance of stimulating and inhibitory T of the inhibitory receptor CD300a, whose gene ranks at the signals is required to efficiently regulate the activation status of top of the human genes that show evidence of positive selec- the immune system. Among several other mechanisms that tion, suggesting a need to maintain some critical function (7). accomplish this mission, this balance is achieved by signals that emanate from cell surface receptors with activating and in- hibitory capabilities (1–3). Some of them are clustered in the Regulation of expression genome as families that consist of paired receptors with ac- Transcripts encoding human CD300a were detected in cells tivating and inhibitory functions. In general, the inhibitory from both the myeloid and lymphoid lineages (4, 5). None- receptors are characterized by the presence of one or more theless, the cell surface expression of CD300a has been dif- ITIMs in their cytoplasmic tail (1, 3), whereas the activating ficult to determine because the majority of available mAbs receptors have a transmembrane charged residue that allows display cross-reactivity and recognize both CD300a and *Immunopathology Group, BioCruces Health Research Institute, Barakaldo 48903, Address correspondence and reprint requests to Dr. Francisco Borrego, Immunopathology Spain; †Cell Therapy and Stem Cell Group, Basque Center for Transfusion and Human Group, BioCruces Health Research Institute, Plaza de Cruces s/n, Barakaldo 48903, Spain. Tissues, Galdakao 48960, Spain; ‡Division of Biotechnology Review and Research-I, E-mail addresses: [email protected] or pacoborregorabasco@ Office of Biotechnology Products Review and Research, Center for Drug Evaluation gmail.com and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993; and x Abbreviations used in this article: ALL, acute lymphoblastic leukemia; CLP, cecal liga- Ikerbasque, Basque Foundation for Science 48903, Bilbao, Spain tion and puncture; KIR, killer cell Ig-like receptor; mDC, myeloid dendritic cell; MFG- Received for publication February 6, 2015. Accepted for publication March 21, 2015. E8, milk-fat globule EGF-factor VIII; pDC, plasmacytoid dendritic cell; PE, phospha- tidylethanolamine; PS, phosphatidylserine; SCF, stem cell factor; SHIP, Src homology This work was supported by the Instituto de Salud Carlos III, Ministerio de Econ- region 2 inositol 59 phosphatase; SHP, Src homology region 2 domain-containing omı´a y Competitividad, Gobierno de Espan˜a (PI13/00889); the Marie Curie Ac- phosphatase; TIM, T cell/transmembrane, Ig, and mucin. tions, Career Integration Grant, European Commission (CIG 631674); and SAIOTEK, Departamento de Desarrollo Econo´mico y Competitividad, Gobierno Vasco (SAIO13- Ó PE13BF005). Copyright 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500304 5054 BRIEF REVIEWS: CD300a RECOGNIZES PS AND PE CD300c on the cell surface (8–10). These are paired receptors the inhibition of hypoxia-inducible factor 1 abolished this up- with inhibitory and activating properties whose extracellular regulation (24). In pDCs, IFN-a production in response to domains exhibit .80% similarity at the amino acid level. TLR7 and TLR9 agonists downregulates the expression of Recently, specific anti-CD300a and anti-CD300c mAbs were CD300a (22), and the eosinophil-derived major basic protein generated (11–13). and eosinophil-derived neurotoxin downregulate it on cord With regard to the lymphoid lineage, CD300a is expressed blood–derived mast cells (19). on the surface of all human NK cells (9, 14) and in subsets of Transcripts encoding mouse CD300a, also known as CLM- T and B cells (8, 10, 15–17). Human naive CD4+ T cells 8 (29), LMIR-1 (30), and MAIR-I (31), are also found in cells express low levels of CD300a, whereas effector/memory cells of the lymphoid and myeloid lineages. On the cell surface, 2 can be subdivided into CD300a+ and CD300a subsets, and it is expressed on the majority of myeloid cells, including 2 2 regulatory T cells are CD300a . Memory CD300a cells macrophages, mast cells, dendritic cells, and granulocytes. tend to proliferate slightly less than do memory CD300a+ On lymphocytes, mouse CD300a is expressed on subsets of cells (8, 15), and the expression of CD300a is associated with B cells, with higher expression on marginal zone B cells (29– Th1 cells that are more polyfunctional and, after stimulation, 32). However, in contrast to human CD300a, it is not upregulate the T-box transcription factor eomesodermin, detected on the surface of unstimulated NK and T cells (31). whereas the IL-17 single-producing CD4+ T cells are mostly In mice, CD300a cell surface expression was detected on 2 CD300a (10, 15). In contrast, in human CD8+ T cells, NK cells after stimulation with IL-12 (31), and peroxisome CD300a expression is coupled to a more cytotoxic phenotype, proliferator-activated receptor b/d directly regulates the ex- Downloaded from suggesting that CD300a is mostly expressed on effector/ pression of the CD300A gene in macrophages (33). In vitro, memory cells, whereas naive CD8+ T cells express low levels IL-33, a