MOJ Immunology

CD160: A Multifunctional Cell Surface Receptor

Editorial CD160 was identified by the monoclonal antibody BY55 as an 83-kDa molecule at the cell surface of human NK cells [1]. Initially, CD160 was recognized as an activating receptor on CD56dim upon engagement by MHC-I molecules on target cells [2,3]. BY55 Volume 1 Issue 4 - 2014 NK cells where it triggers cytokine production and cytotoxicity Christian Schmitt, Anne Marie-Cardine, Jerome Giustiniani, Philippe Le antibody recognized a glycosylphosphatidylinositol (GPI)-linked Bouteiller and Armand Bensussan* moleculeMore consisting recently otherof a single isoforms extracellular were unveiled Ig-like domain. including a Hopital Saint Louis, INSERM U976, Equerre Bazin, 1 avenue Claude Vellefaux, F-75010, Paris, France

*Corresponding author: Armand Bensussan, isoformstransmembrane were detected (TM) form as alternativeand decoy receptors transcripts lacking mRNA the or Ig- by like domain, essential for ligand binding. Unfortunately these the native transmembrane form at the cell surface. CD160 can Hopital Saint Louis, INSERM U976, Equerre Bazin, 1 Western blot, but until now no antibody is able to recognize avenue Claude Vellefaux, F-75010, Paris, France, Tel: also be found as a soluble form in the serum and extracellular +331-537-220-81; Fax: +331-537-220-51; Email: Received: | Published: 20, 2014 September 19, 2014 September [4].fluids. This This soluble soluble CD160 form impairedis produced NK from activation, the CD160-GPI possibly by a juxta-membrane enzymatic cleavage by a phospholipase-D competing for binding to MHC-I molecules. CD160 was not only of co-regulatory signals. Besides, as CD160 expression appears found to be expressed on NK cells but it was also detected at the tightly regulated in lymphocytes, analysis of the mechanisms surface of CD8 T cells [5,6], a minor subset of circulating CD4 controlling expression were of interest. CD160 have been clone on human 1 [16]. Analysis of its promoter intraepithelial T cells, activated endothelial cells [10], and mast T cells [7], cutaneous T cells [8,9], γδ T lymphocytes, intestinal in its minimal promoter region. Among these the AML1/RUNX1 transcriptionalregion identified regulator several wasconserved shown transcription to be essential binding for CD160 sites bothcells [11].at the Of note, whereas and mRNA human level B [12]. cells lack CD160 expression, B-cell chronic lymphocytic leukaemia (CLL) expresses CD160 expression [17]. RUNX family play an important role in However, despite this wide CD160 expression, it seems that the NK cell differentiation [18]. the trans-membrane CD160 isoform expression is restricted to the NK compartment. CD160 was also found expressed in KIR binding factor controlling clonally expressed KIR duringFor NK example, cell development AML-2 was [19] identified and AML-1 as the participates predominant to [13], where, as in humans, it interacts with classical and non- classicalmouse NK MHC-I cells and CD8+CD1d activated[14]. Triggering and memory CD160 T at lymphocytes the surface the transcriptional control of important genes implicated in of the various human cell types resulting in either cell activation or inhibition. This is particularly true for T lymphocytes where in NK cells where CD160 is present at the surface of CD56dim, CD160cytotoxicity expression such as is IL2, fairly IFN-γ well and associated granzyme with B [20,21]. cytotoxic Like T on CD8 T-cell activation upon binding to MHC-I ligands or have a co-inhibitoryCD160-GPI was role reported on CD4 T-cellto either activation mediate upon co-stimulatory binding to herpes effect effector-memory T cell population, representing about 30 % of or effector-memory lymphocytes. In the skin a resident CD4+ [15]. This opposite co-regulatory function of CD160 is intriguing virus entry mediator (HVEM), an alternative ligand of CD160 Thesethe cutaneous cells have CD4+ a cytotoxic T cells potential have been and are identified probably that important express CD160 and skin addressing molecules such as CLA and CCR4 [9]. tobut mediate that may its dependfunctions. on It the is clear nature that of the molecular unknown signallingstructure ofmolecules the CD160 to whichreceptor the is CD160-GPI important forreceptor its recognition may associate capacity. with, for skin immunosurveillance but the precise regulatory role of CD160On in the this other context hand is still CD160 unknown. expression has been shown on growing, but not quiescent endothelial cells [10]. Here CD160 fromIn Western its amino-acid blot CD160-GPI sequence. is detected, The same in reducing observations conditions, have as an 83 and a 50 kDa bands, far from the 17.5 kDa estimated was clearly an inhibitory receptor as its cross-linking lead to CD160an antiangiogenic receptor. More effect studies in several are needed model to of fully neovascularization understand the isbeen therefore made for present the CD160-TM at the cell detected surface as as 100 multimers kDa molecule possibly in [22]. This demonstrates the multifunctional effect of the amazing mainlyWestern a blottrimer for and an estimated at lower frequency molecular a mass dimer. of This25.6 uncertaintykDa. CD160 about the true CD160 molecular complexes expressed at the specificitiesReferences and the functions of this receptor and its isoforms. 1. proper ligand binding capacity of CD160 and its function in terms al. (1994) BY55 monoclonal antibody delineates within human cord lymphocyte surface needs to be clarified to understand the Bensussan A, Gluckman E, el Marsafy S, Schiavon V, Mansur IG, et

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blood and bone marrow lymphocytes distinct cell subsets mediating 12. Liu FT, Giustiniani J, Farren T, Jia L, Bensussan A, et al. (2010) CD160

2. cytotoxic activity. Proc Natl Acad Sci U S A 91(19): 9136-9140. signaling mediates PI3K-dependent survival and growth signals in (2004) Cutting edge: engagement of CD160 by its HLA-C physiological 13. chronic lymphocytic leukemia. Blood 115(15): 3079-3088. Barakonyi A, Rabot M, Marie-Cardine A, Aguerre-Girr M, Polgar B, et al. Tsujimura K, Obata Y, Matsudaira Y, Nishida K, Akatsuka Y, et al. peripheral blood NK cell subset. J Immunol 173(9): 5349-5354. Immunol Lett 106(1): 48-56. ligand triggers a unique cytokine profile secretion in the cytotoxic (2006) Characterization of murine CD160+ CD8+ T lymphocytes. 3. 14.

Le Bouteiller P, Barakonyi A, Giustiniani J, Lenfant F, Marie-Cardine A, classicalMaeda M, and Carpenito nonclassical C, Russell MHC RC,class Dasanjh I and regulates J, Veinotte NK LL, cell et activation. al. (2005) et al. (2002) Engagement of CD160 receptor by HLA-C is a triggering JMurine Immunol CD160, 175(7): Ig-like 4426-4432. receptor on NK cells and NKT cells, recognizes mechanism used by circulating natural killer (NK) cells to mediate 15. 4. cytotoxicity.Giustiniani J, Proc Marie-Cardine Natl Acad Sci A, U Bensussan S A 99(26): A 16963-16968. (2007) A soluble form bidirectional switch regulating T-cell activation. Immunol Rev 229(1): 244-258.Cai G, Freeman GJ (2009) The CD160, BTLA, LIGHT/HVEM pathway: a activated NK lymphocytes and inhibits cell-mediated cytotoxicity. J Immunolof the MHC 178(3): class 1293-1300.I-specific CD160 receptor is released from human 16. al. (1998) Cloning of BY55, a novel Ig superfamily member expressed 5. onAnumanthan NK cells, CTL, A, Bensussan and intestinal A, Boumsell intraepithelial L, Christ lymphocytes. AD, Blumberg J Immunol RS, et Nikolova MH, Muhtarova MN, Taskov HB, Kostov K, Vezenkov L, et al. 161: 2780-2790. (2005) The CD160+ CD8high cytotoxic T cell subset correlates with 17. 6. response to HAART in HIV-1+ patients. Cell Immunol 237(2): 96-105. analysis of the human CD160 promoter: implication of a potential co-expression of 2B4 (CD244) and CD160 delineates a subpopulation AML-1Schmitt binding C, Ghazi site B, inBellier promoter F, Bensussan activation. A Genes(2009) Immun Identification 10(7): 616- and Rey J, Giustiniani J, Mallet F, Schiavon V, Boumsell L, et al. (2006) The 623. of human CD8+ T cells with a potent CD160-mediated cytolytic 18. 7. effector function. Eur J Immunol 36(9): 2359-2366. proteins are involved in regulation of CD122, Ly49 family and IFN- gammaOhno S, expression Sato T, Kohu during K, TakedaNK cell K,differentiation. Okumura K, Int et al.Immunol (2008) 20(1): Runx withCai G, herpesvirus Anumanthan entry A, Brownmediator. JA, NatGreenfield Immunol EA, 9(2): Zhu 176-185. B, et al. (2008) 71-79. CD160 inhibits activation of human CD4+ T cells through interaction 8. 19.

Abecassis S, Giustiniani J, Meyer N, Schiavon V, Ortonne N, et al. (2007) Trompeter HI, Gomez-Lozano N, Santourlidis S, Eisermann B, Wernet 127(5):Identification 1161-1166. of a novel CD160+ CD4+ T-lymphocyte subset in the P, et al. (2005) Three structurally and functionally divergent kinds of skin: a possible role for CD160 in skin inflammation. J Invest Dermatol 4135-4143.promoters regulate expression of clonally distributed killer cell Ig- 9. like receptors (KIR), of KIR2DL4, and of KIR3DL3. J Immunol 174(7): 20. toSako delineate N, Schiavon a unique V, Bounfour CD4 T-lymphocyte T, Dessirier subset V, Ortonne in normal N, etand al. mycosis (2014) Foxp3 controls regulatory T-cell function by interacting with AML1/ Membrane expression of NK receptors CD160 and CD158k contributes Runx1.Ono M, NatureYaguchi 446(7136): H, Ohkura N,685-689. Kitabayashi I, Nagamura Y, et al. (2007) 21. 10. fungoides skin. Cytometry A doi: 10.1002/cyto.a.22512. Wargnier A, Legros-Maida S, Bosselut R, Bourge JF, Lafaurie C, et al. andFons by P, direct Chabot binding S, Cartwright to CD160 JE, Lenfantreceptor F, expressed L’Faqihi F, by et endothelial al. (2006) Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway (1995) Identification of human granzyme B promoter regulatory cells. Blood 108(8): 2608-2615. elements interacting with activated T-cell-specific proteins: 11. Ortonne N, Ram-Wolff C, Giustiniani J, Marie-Cardine A, Bagot M, et implication of Ikaros and CBF binding sites in promoter activation. 22. Proc Natl Acad Sci U S A 92(15): 6930-6934. anchored isoform of CD160. J Invest Dermatol 131(4): 916-924. Chabot S, Jabrane-Ferrat N, Bigot K, Tabiasco J, Provost A, et al. (2011) al. (2011) Human and mouse mast cells express and secrete the GPI- A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor. J Exp Med 208(5): 973-986.

Citation: 1(4): 00021. DOI: 10.15406/moji.2014.01.00021 Schmitt C, Marie-Cardine A, Giustiniani J, Bouteiller PL, Bensussan A (2014) CD160: A Multifunctional Cell Surface Receptor. MOJ Immunol