, Volume 64, Issue 1, pp 39–47 | Cite as

Specific lipid recognition is a general feature of CD300 and TREM molecules

  • John P. Cannon
  • Marci O’Driscoll
  • Gary W. Litman
Original Paper


CD300, triggering receptor expressed on myeloid cells (TREM), and TREM-like (TREML) receptors are important regulators of the mammalian immune response. Homologs of these receptors, which occur in activating and inhibitory transmembrane forms as well as soluble variants, are found throughout the jawed vertebrates. Specific ligands for most members of these receptor families remain elusive. We report here that at least 11 separate receptors from the CD300, TREM, and TREML families engage in robust and specific interactions with major polar lipids found in prokaryotic and eukaryotic cell membranes. Both soluble and membrane-bound receptor forms exhibit lipid interactions in the solid phase as well as in a physiological signaling context. Overlapping but distinctive patterns of receptor specificity suggest that the CD300/TREM system as a whole may discriminate immunological stimuli based on lipid signatures, thereby influencing downstream responses.


Innate immunity Ligand Phospholipid Immunoglobulin superfamily Evolution 



We would like to thank Barbara Pryor for editorial assistance and Larry Dishaw for helpful conversation regarding this work. This work was supported by National Institutes of Health grants AI23338 and AI57559 (to GWL) and an All Children’s Hospital Foundation grant (to JPC).

Supplementary material

251_2011_562_MOESM1_ESM.pdf (309 kb)
ESM 1 (PDF 308 kb)


  1. Aboagye EO, Bhujwalla ZM (1999) Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Res 59:80–84PubMedGoogle Scholar
  2. Alphen WV, Lugtenberg B (1977) Influence of osmolarity of the growth medium on the outer membrane protein pattern of Escherichia coli. J Bacteriol 131:623–630PubMedGoogle Scholar
  3. Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M et al (2006) Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol 2:2006–2008CrossRefGoogle Scholar
  4. Barrow AD, Trowsdale J (2008) The extended human leukocyte receptor complex: diverse ways of modulating immune responses. Immunol Rev 224:98–123PubMedCrossRefGoogle Scholar
  5. Bhujwalla ZM, Aboagye EO, Gillies RJ, Chacko VP, Mendola CE, Backer JM (1999) Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn Reson Med 41:897–903PubMedCrossRefGoogle Scholar
  6. Cannon JP, Haire RN, Mueller MG, Litman RT, Eason DD, Tinnemore D et al (2006) Ancient divergence of a complex family of immune-type receptor genes. Immunogenet 58:362–373CrossRefGoogle Scholar
  7. Cannon JP, Haire RN, Magis AT, Eason DD, Winfrey KN, Hernandez Prada JA et al (2008) A bony fish immunological receptor of the NITR multigene family mediates allogeneic recognition. Immunity 29:228–237PubMedCrossRefGoogle Scholar
  8. Cannon JP, O'Driscoll ML, Litman GW (2011) Construction, expression and purification of chimeric protein reagents based on immunoglobulin Fc regions. Methods Mol Biol 748:51–67PubMedCrossRefGoogle Scholar
  9. Charles JF, Humphrey MB, Zhao X, Quarles E, Nakamura MC, Aderem A et al (2008) The innate immune response to Salmonella enterica serovar Typhimurium by macrophages is dependent on TREM2-DAP12. Infect Immun 76:2439–2447PubMedCrossRefGoogle Scholar
  10. Clark GJ, Ju X, Tate C, Hart DN (2009) The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends Immunol 30:209–217PubMedCrossRefGoogle Scholar
  11. Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE (2003) Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 171:594–599PubMedGoogle Scholar
  12. Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46PubMedCrossRefGoogle Scholar
  13. Freeman GJ, Casasnovas JM, Umetsu DT, Dekruyff RH (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235:172–189PubMedGoogle Scholar
  14. Fujimoto M, Takatsu H, Ohno H (2006) CMRF-35-like molecule-5 constitutes novel paired receptors, with CMRF-35-like molecule-1, to transduce activation signal upon association with FcRgamma. Int Immunol 18:1499–1508PubMedCrossRefGoogle Scholar
  15. Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci U S A 105:10495–10500PubMedCrossRefGoogle Scholar
  16. Hemmi H, Idoyaga J, Suda K, Suda N, Kennedy K, Noda M et al (2009) A new triggering receptor expressed on myeloid cells (Trem) family member, Trem-like 4, binds to dead cells and is a DNAX activation protein 12-linked marker for subsets of mouse macrophages and dendritic cells. J Immunol 182:1278–1286PubMedGoogle Scholar
  17. Izawa K, Kitaura J, Yamanishi Y, Matsuoka T, Oki T, Shibata F et al (2007) Functional analysis of activating receptor LMIR4 as a counterpart of inhibitory receptor LMIR3. J Biol Chem 282:17997–18008PubMedCrossRefGoogle Scholar
  18. Jain M, Petzold CJ, Schelle MW, Leavell MD, Mougous JD, Bertozzi CR et al (2007) Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling. Proc Natl Acad Sci U S A 104:5133–5138PubMedCrossRefGoogle Scholar
  19. Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D et al (2010) Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 5:e13950PubMedCrossRefGoogle Scholar
  20. Klesney-Tait J, Turnbull IR, Colonna M (2006) The TREM receptor family and signal integration. Nat Immunol 7:1266–1273PubMedCrossRefGoogle Scholar
  21. Kobayashi N, Karisola P, Pena-Cruz V, Dorfman DM, Jinushi M, Umetsu SE et al (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927–940PubMedCrossRefGoogle Scholar
  22. Laun K, Coggill P, Palmer S, Sims S, Ning Z, Ragoussis J et al (2006) The leukocyte receptor complex in chicken is characterized by massive expansion and diversification of immunoglobulin-like Loci. PLoS Genet 2:e73PubMedCrossRefGoogle Scholar
  23. Leitner J, Klauser C, Pickl WF, Stockl J, Majdic O, Bardet AF et al (2009) B7-H3 is a potent inhibitor of human T-cell activation: no evidence for B7-H3 and TREML2 interaction. Eur J Immunol 39:1754–1764PubMedCrossRefGoogle Scholar
  24. Litman GW, Cannon JP, Dishaw LJ (2005) Reconstructing immune phylogeny: new perspectives. Nat Rev Immunol 5:866–879PubMedCrossRefGoogle Scholar
  25. Martinez-Barriocanal A, Sayos J (2006) Molecular and functional characterization of CD300b, a new activating immunoglobulin receptor able to transduce signals through two different pathways. J Immunol 177:2819–2830PubMedGoogle Scholar
  26. Martinez-Barriocanal A, Comas-Casellas E, Schwartz S Jr, Martin M, Sayos J (2010) CD300 heterocomplexes, a new and family-restricted mechanism for myeloid cell signaling regulation. J Biol Chem 285:41781–41794PubMedCrossRefGoogle Scholar
  27. Medzhitov R (2009) Approaching the asymptote: 20 years later. Immunity 30:766–775PubMedCrossRefGoogle Scholar
  28. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439PubMedCrossRefGoogle Scholar
  29. N'Diaye EN, Branda CS, Branda SS, Nevarez L, Colonna M, Lowell C et al (2009) TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol 184:215–223PubMedCrossRefGoogle Scholar
  30. Palm NW, Medzhitov R (2009) Pattern recognition receptors and control of adaptive immunity. Immunol Rev 227:221–233PubMedCrossRefGoogle Scholar
  31. Radhakrishnan S, Arneson LN, Upshaw JL, Howe CL, Felts SJ, Colonna M et al (2008) TREM-2 mediated signaling induces antigen uptake and retention in mature myeloid dendritic cells. J Immunol 181:7863–7872PubMedGoogle Scholar
  32. Santiago C, Ballesteros A, Martinez-Munoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM (2007) Structures of T cell immunoglobulin mucin protein 4 show a metal-ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27:941–951PubMedCrossRefGoogle Scholar
  33. Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Bordignon PP, Meldolesi J (2009) The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 110:284–294PubMedCrossRefGoogle Scholar
  34. Steinberg BE, Grinstein S (2008) Pathogen destruction versus intracellular survival: the role of lipids as phagosomal fate determinants. J Clin Invest 118:2002–2011PubMedCrossRefGoogle Scholar
  35. Takegahara N, Takamatsu H, Toyofuku T, Tsujimura T, Okuno T, Yukawa K, Mizui M et al (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8:615–622PubMedCrossRefGoogle Scholar
  36. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L et al (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177:3520–3524PubMedGoogle Scholar
  37. Umemoto E, Tanaka T, Kanda H, Jin S, Tohya K, Otani K et al (2006) Nepmucin, a novel HEV sialomucin, mediates L-selectin-dependent lymphocyte rolling and promotes lymphocyte adhesion under flow. J Exp Med 203:1603–1614PubMedCrossRefGoogle Scholar
  38. Viertlboeck BC, Schmitt R, Gobel TW (2006) The chicken immunoregulatory receptor families SIRP, TREM, and CMRF35/CD300L. Immunogenet 58:180–190CrossRefGoogle Scholar
  39. Washington AV, Gibot S, Acevedo I, Gattis J, Quigley L, Feltz R et al (2009) TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans. J Clin Invest 119:1489–1501PubMedCrossRefGoogle Scholar
  40. Xi H, Katschke KJ Jr, Helmy KY, Wark PA, Kljavin N, Clark H et al (2010) Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1. J Exp Med 207:7–16PubMedCrossRefGoogle Scholar
  41. Yamanishi Y, Kitaura J, Izawa K, Kaitani A, Komeno Y, Nakamura M et al (2010) TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury. J Exp Med 207:1501–1511PubMedCrossRefGoogle Scholar
  42. Yotsumoto K, Okoshi Y, Shibuya K, Yamazaki S, Tahara-Hanaoka S, Honda S et al (2003) Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II, regulate mast cell and macrophage activation. J Exp Med 198:223–233PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • John P. Cannon
    • 1
  • Marci O’Driscoll
    • 2
  • Gary W. Litman
    • 1
    • 2
  1. 1.Department of Pediatrics, Children’s Research InstituteUniversity of South FloridaSt. PetersburgUSA
  2. 2.Department of Molecular GeneticsAll Children’s HospitalSt. PetersburgUSA

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