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Immunology

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Received: January 01, 1970 | Published: ,

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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 NK cells where it triggers cytokine production and cytotoxicity upon engagement by MHC-I molecules on target cells.2,3 BY55 antibody recognized a glycosylphosphatidylinositol (GPI)-linked molecule consisting of a single extracellular Ig-like domain.

More recently other isoforms were unveiled including a transmembrane (TM) form and decoy receptors lacking the Ig-like domain, essential for ligand binding. Unfortunately these isoforms were detected as alternative transcripts mRNA or by Western blot, but until now no antibody is able to recognize the native transmembrane form at the cell surface. CD160 can also be found as a soluble form in the serum and extracellular fluids. This soluble form is produced from the CD160-GPI by a juxta-membrane enzymatic cleavage by a phospholipase-D.4 This soluble CD160 impaired NK activation, possibly by competing for binding to MHC-I molecules. CD160 was not only found to be expressed on NK cells but it was also detected at the surface of CD8 T cells.5,6 a minor subset of circulating CD4 T cells,7 cutaneous T cells,8,9 γδ T lymphocytes, intestinal intraepithelial T cells, activated endothelial cells,10 and mast cells.11 Of note, whereas human B cells lack CD160 expression, B-cell chronic lymphocytic leukaemia (CLL) expresses CD160 both at the protein and mRNA level.12

However, despite this wide CD160 expression, it seems that the trans-membrane CD160 isoform expression is restricted to the NK compartment. CD160 was also found expressed in mouse NK cells and CD8+ activated and memory T lymphocytes,13 where, as in humans, it interacts with classical and non-classical MHC-I and CD1d.14 Triggering CD160 at the surface of the various human cell types resulting in either cell activation or inhibition. This is particularly true for T lymphocytes where CD160-GPI was reported to either mediate co-stimulatory effect on CD8 T-cell activation upon binding to MHC-I ligands or have a co-inhibitory role on CD4 T-cell activation upon binding to herpes virus entry mediator (HVEM), an alternative ligand of CD160.15 This opposite co-regulatory function of CD160 is intriguing but that may depend on the nature of the unknown signalling molecules to which the CD160-GPI receptor may associate with, to mediate its functions. It is clear that the molecular structure of the CD160 receptor is important for its recognition capacity.

In Western blot CD160-GPI is detected, in reducing conditions, as an 83 and a 50 kDa bands, far from the 17.5 kDa estimated from its amino-acid sequence. The same observations have been made for the CD160-TM detected as 100 kDa molecule in Western blot for an estimated molecular mass of 25.6 kDa. CD160 is therefore present at the cell surface as multimers possibly mainly a trimer and at lower frequency a dimer. This uncertainty about the true CD160 molecular complexes expressed at the lymphocyte surface needs to be clarified to understand the proper ligand binding capacity of CD160 and its function in terms of co-regulatory signals. Besides, as CD160 expression appears tightly regulated in lymphocytes, analysis of the mechanisms controlling gene expression were of interest. CD160 have been clone on human chromosome 1.16 Analysis of its promoter region identified several conserved transcription binding sites in its minimal promoter region. Among these the AML1/RUNX1 transcriptional regulator was shown to be essential for CD160 expression.17 RUNX family proteins play an important role in the NK cell differentiation.18

For example, AML-2 was identified as the predominant KIR binding factor controlling clonally expressed KIR genes during NK cell development19 and AML-1 participates to the transcriptional control of important genes implicated in cytotoxicity such as IL2, IFN-γ and granzyme B.20,21 Like in NK cells where CD160 is present at the surface of CD56dim, CD160 expression is fairly well associated with cytotoxic T or effector-memory lymphocytes. In the skin a resident CD4+ effector-memory T cell population, representing about 30 % of the cutaneous CD4+ T cells have been identified that express CD160 and skin addressing molecules such as CLA and CCR4.9 These cells have a cytotoxic potential and are probably important for skin immunosurveillance but the precise regulatory role of CD160 in this context is still unknown.

On the other hand CD160 expression has been shown on growing, but not quiescent endothelial cells.10 Here CD160 was clearly an inhibitory receptor as its cross-linking lead to an antiangiogenic effect in several model of neovascularisation.22 This demonstrates the multifunctional effect of the amazing CD160 receptor. More studies are needed to fully understand the specificities and the functions of this receptor and its isoforms.

Acknowledgments

None.

Conflicts of interest

There is no conflict of interest.

Funding

None.

References

  1. Bensussan A, Gluckman E, el Marsafy S, et al. BY55 monoclonal antibody delineates within human cord blood and bone marrow lymphocytes distinct cell subsets mediating cytotoxic activity. Proc Natl Acad Sci U S A. 1994;91(19): 9136–9140.
  2. Barakonyi A, Rabot M, Marie–Cardine A, et al. Cutting edge: engagement of CD160 by its HLA–C physiological ligand triggers a unique cytokine profile secretion in the cytotoxic peripheral blood NK cell subset. J Immunol. 2004;173(9):5349–5354.
  3. Le Bouteiller P, Barakonyi A, Giustiniani J, et al. Engagement of CD160 receptor by HLA–C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity. Proc Natl Acad Sci U S A. 2002;99(26):16963–16968.
  4. Giustiniani J, Marie–Cardine A, Bensussan A. A soluble form of the MHC class I–specific CD160 receptor is released from human activated NK lymphocytes and inhibits cell–mediated cytotoxicity. J Immunol. 2007;178(3):1293–1300.
  5. Nikolova MH, Muhtarova MN, Taskov HB, et al. The CD160+ CD8high cytotoxic T cell subset correlates with response to HAART in HIV–1+ patients. Cell Immunol. 2005;237(2): 96–105.
  6. Rey J, Giustiniani J, Mallet F, et al. The co–expression of 2B4 (CD244) and CD160 delineates a subpopulation of human CD8+ T cells with a potent CD160–mediated cytolytic effector function. Eur J Immunol. 2006;36(9):2359–2366.
  7. Cai G, Anumanthan A, Brown JA, et al. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol. 2008;9(2):176–185.
  8. Abecassis S, Giustiniani J, Meyer N, et al. Identification of a novel CD160+ CD4+ T–lymphocyte subset in the skin: a possible role for CD160 in skin inflammation. J Invest Dermatol. 2007;127(5):1161–1166.
  9. Sako N, Schiavon V, Bounfour T, et al. Membrane expression of NK receptors CD160 and CD158k contributes to delineate a unique CD4 T–lymphocyte subset in normal and mycosis fungoides skin. Cytometry A. 2014.
  10. Fons P, Chabot S, Cartwright JE, et al. Soluble HLA–G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells. Blood. 2006;108(8):2608–2615.
  11. Ortonne N, Ram–Wolff C, Giustiniani J, et al. Human and mouse mast cells express and secrete the GPI–anchored isoform of CD160. J Invest Dermatol. 2011;131(4):916–924.
  12. Liu FT, Giustiniani J, Farren T, et al. CD160 signaling mediates PI3K–dependent survival and growth signals in chronic lymphocytic leukemia. Blood. 2010;115(15):3079–3088.
  13. Tsujimura K, Obata Y, Matsudaira Y, et al. Characterization of murine CD160+ CD8+ T lymphocytes. Immunol Lett. 2006;106(1):48–56.
  14. Maeda M, Carpenito C, Russell RC, et al. Murine CD160, Ig–like receptor on NK cells and NKT cells, recognizes classical and nonclassical MHC class I and regulates NK cell activation. J Immunol. 2005;175(7):4426–4432.
  15. Cai G, Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T–cell activation. Immunol Rev. 2009;229(1):244–258.
  16. Anumanthan A, Bensussan A, Boumsell L, et al. Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes. J Immunol. 19988;161:2780–2790.
  17. Schmitt C, Ghazi B, Bellier F, Bensussan A. Identification and analysis of the human CD160 promoter: implication of a potential AML–1 binding site in promoter activation. Genes Immun. 2009;10(7):616–623.
  18. Ohno S, Sato T, Kohu K, et al. Runx proteins are involved in regulation of CD122, Ly49 family and IFN–gamma expression during NK cell differentiation. Int Immunol. 2008;20(1):71–79.
  19. Trompeter HI, Gomez–Lozano N, Santourlidis S, et al. Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig–like receptors (KIR), of KIR2DL4, and of KIR3DL3. J Immunol. 2005;174(7):4135–4143.
  20. Ono M, Yaguchi H, Ohkura N, et al. Foxp3 controls regulatory T–cell function by interacting with AML1/Runx1. Nature. 2007;446(7136): 685–689.
  21. Wargnier A, Legros–Maida S, Bosselut R, et al. Identification of human granzyme B promoter regulatory elements interacting with activated T–cell–specific proteins: implication of Ikaros and CBF binding sites in promoter activation. Proc Natl Acad Sci U S A. 1995;92(15):6930–6934.
  22. Chabot S, Jabrane–Ferrat N, Bigot K, et al. A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor. J Exp Med. 2011;208(5): 973–986.
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