Balancing natural killer cell activation through paired receptors (original) (raw)

• Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nature Immunol. 9, 503–510 (2008).
  CAS Google Scholar
• Long, E. O., Kim, H. S., Liu, D., Peterson, M. E. & Rajagopalan, S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol. 31, 227–258 (2013). This is an outstanding and comprehensive review on the control of NK cell functions through activating and inhibitory receptors.
  CAS PubMed Google Scholar
• Karre, K. Natural killer cell recognition of missing self. Nature Immunol. 9, 477–480 (2008).
  Google Scholar
• Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nature Immunol. 9, 495–502 (2008).
  CAS Google Scholar
• Chan, C. J. et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nature Immunol. 15, 431–438 (2014). This is the first paper showing a crucial role for CD96 in limiting NK cell functions in vivo using Cd96 −/− mice.
  CAS Google Scholar
• Stanietsky, N. et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc. Natl Acad. Sci. USA 106, 17858–17863 (2009). This study shows a potential role for TIGIT in limiting human NK cell cytotoxicity.
  CAS PubMed Google Scholar
• Gilfillan, S. et al. DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J. Exp. Med. 205, 2965–2973 (2008).
  CAS PubMed PubMed Central Google Scholar
• Shibuya, A. et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4, 573–581 (1996).
  CAS PubMed Google Scholar
• Bottino, C. et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 198, 557–567 (2003). References 8 and 9 report that CD226 engagement by its ligands, CD112 and CD155, on target cells stimulates NK cell cytolytic functions.
  CAS PubMed PubMed Central Google Scholar
• Sakisaka, T. & Takai, Y. Biology and pathology of nectins and nectin-like molecules. Curr. Opin. Cell Biol. 16, 513–521 (2004).
  CAS PubMed Google Scholar
• Chan, C. J., Smyth, M. J. & Martinet, L. Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ. 21, 5–14 (2014).
  CAS PubMed Google Scholar
• Bernhardt, G. TACTILE becomes tangible: CD96 discloses its inhibitory peculiarities. Nature Immunol. 15, 406–408 (2014).
  CAS Google Scholar
• Minton, K. Natural killer cells: a TACTILE restraint. Nature Rev. Immunol. 14, 285 (2014).
  Google Scholar
• Yu, X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nature Immunol. 10, 48–57 (2009). This is the first identification of TIGIT and its inhibitory functions through its interaction with CD155.
  CAS Google Scholar
• Seth, S. et al. Heterogeneous expression of the adhesion receptor CD226 on murine NK and T cells and its function in NK-mediated killing of immature dendritic cells. J. Leukoc. Biol. 86, 91–101 (2009).
  CAS PubMed Google Scholar
• Tahara-Hanaoka, S. et al. Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112). Int. Immunol. 16, 533–538 (2004).
  CAS PubMed Google Scholar
• Liu, J. et al. Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J. Immunol. 188, 5511–5520 (2012).
  CAS PubMed Google Scholar
• Hou, S. et al. CD226 protein is involved in immune synapse formation and triggers natural killer (NK) cell activation via its first extracellular domain. J. Biol. Chem. 289, 6969–6977 (2014).
  CAS PubMed PubMed Central Google Scholar
• Tahara-Hanaoka, S. et al. Tumor rejection by the poliovirus receptor family ligands of the DNAM-1 (CD226) receptor. Blood 107, 1491–1496 (2006).
  CAS PubMed Google Scholar
• Stanietsky, N. et al. Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur. J. Immunol. 43, 2138–2150 (2013).
  CAS PubMed PubMed Central Google Scholar
• Boles, K. S. et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur. J. Immunol. 39, 695–703 (2009).
  CAS PubMed PubMed Central Google Scholar
• Levin, S. D. et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur. J. Immunol. 41, 902–915 (2011).
  CAS PubMed PubMed Central Google Scholar
• Georgiev, H. et al. To the Editor: TIGIT versus CD226: hegemony or coexistence? Eur. J. Immunol. 44, 307–308 (2014).
  CAS PubMed Google Scholar
• Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014). This study shows that TIGIT is expressed by PD1+ exhausted tumour-infiltrating T cells and that targeting these receptors with monoclonal antibodies represents a promising strategy to restore CD8+ T cell functions in cancer or in chronic infectious disease.
  CAS PubMed Google Scholar
• Wang, P. L., O'Farrell, S., Clayberger, C. & Krensky, A. M. Identification and molecular cloning of tactile. A novel human T cell activation antigen that is a member of the Ig gene superfamily. J. Immunol. 148, 2600–2608 (1992).
  CAS PubMed Google Scholar
• Meyer, D. et al. CD96 interaction with CD155 via its first Ig-like domain is modulated by alternative splicing or mutations in distal Ig-like domains. J. Biol. Chem. 284, 2235–2244 (2009).
  CAS PubMed Google Scholar
• Seth, S. et al. The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochem. Biophys. Res. Commun. 364, 959–965 (2007).
  CAS PubMed Google Scholar
• de Andrade, L. F., Smyth, M. J. & Martinet, L. DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. Immunol. Cell Biol. 92, 237–244 (2014).
  PubMed Google Scholar
• Fuchs, A., Cella, M., Giurisato, E., Shaw, A. S. & Colonna, M. Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J. Immunol. 172, 3994–3998 (2004).
  CAS PubMed Google Scholar
• Stengel, K. F. et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires _cis_-trans receptor clustering. Proc. Natl Acad. Sci. USA 109, 5399–5404 (2012).
  CAS PubMed Google Scholar
• Liu, S. et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 20, 456–464 (2013).
  CAS PubMed Google Scholar
• Orange, J. S. Formation and function of the lytic NK-cell immunological synapse. Nature Rev. Immunol. 8, 713–725 (2008).
  CAS Google Scholar
• Ramsbottom, K. M. et al. Cutting edge: DNAX accessory molecule 1-deficient CD8+ T cells display immunological synapse defects that impair antitumor immunity. J. Immunol. 192, 553–557 (2014).
  CAS PubMed Google Scholar
• Lagrue, K. et al. The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse. Immunol. Rev. 256, 203–221 (2013).
  CAS PubMed Google Scholar
• Gross, C. C., Brzostowski, J. A., Liu, D. & Long, E. O. Tethering of intercellular adhesion molecule on target cells is required for LFA-1-dependent NK cell adhesion and granule polarization. J. Immunol. 185, 2918–2926 (2010).
  CAS PubMed Google Scholar
• Vyas, Y. M. et al. Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J. Immunol. 167, 4358–4367 (2001).
  CAS PubMed Google Scholar
• Shibuya, K. et al. CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J. Exp. Med. 198, 1829–1839 (2003).
  CAS PubMed PubMed Central Google Scholar
• Ralston, K. J. et al. The LFA-1-associated molecule PTA-1 (CD226) on T cells forms a dynamic molecular complex with protein 4.1G and human discs large. J. Biol. Chem. 279, 33816–33828 (2004).
  CAS PubMed Google Scholar
• Shibuya, K. et al. Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 11, 615–623 (1999).
  CAS PubMed Google Scholar
• Bryceson, Y. T., Ljunggren, H. G. & Long, E. O. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114, 2657–2666 (2009).
  CAS PubMed PubMed Central Google Scholar
• Lozano, E., Dominguez-Villar, M., Kuchroo, V. & Hafler, D. A. The TIGIT/CD226 axis regulates human T cell function. J. Immunol. 188, 3869–3875 (2012).
  CAS PubMed PubMed Central Google Scholar
• Lozano, E., Joller, N., Cao, Y., Kuchroo, V. K. & Hafler, D. A. The CD226/CD155 interaction regulates the proinflammatory (TH1/TH17)/anti-inflammatory (TH2) balance in humans. J. Immunol. 191, 3673–3680 (2013).
  CAS PubMed Google Scholar
• Bi, J. et al. TIGIT safeguards liver regeneration through regulating NK cell-hepatocyte crosstalk. Hepatology 60, 1389–1398 (2014).
  CAS PubMed Google Scholar
• Li, M. et al. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling. J. Biol. Chem. 289, 17647–17657 (2014).
  CAS PubMed PubMed Central Google Scholar
• Pende, D. et al. Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction. Blood 107, 2030–2036 (2006).
  CAS PubMed Google Scholar
• Maier, M. K. et al. The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens. Eur. J. Immunol. 37, 2214–2225 (2007).
  CAS PubMed Google Scholar
• Kamran, N. et al. Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigen-presenting cells. PLoS ONE 8, e54406 (2013).
  CAS PubMed PubMed Central Google Scholar
• Oda, T., Ohka, S. & Nomoto, A. Ligand stimulation of CD155alpha inhibits cell adhesion and enhances cell migration in fibroblasts. Biochem. Biophys. Res. Commun. 319, 1253–1264 (2004).
  CAS PubMed Google Scholar
• Sato, T. et al. Common signaling pathway is used by the _trans_-interaction of Necl-5/Tage4/PVR/CD155 and nectin, and of nectin and nectin during the formation of cell-cell adhesion. Cancer Sci. 96, 578–589 (2005).
  CAS PubMed Google Scholar
• Walzer, T., Dalod, M., Robbins, S. H., Zitvogel, L. & Vivier, E. Natural-killer cells and dendritic cells: “l'union fait la force”. Blood 106, 2252–2258 (2005).
  CAS PubMed Google Scholar
• Morandi, B. et al. Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response. PLoS ONE 7, e39170 (2012).
  CAS PubMed PubMed Central Google Scholar
• Zingoni, A., Ardolino, M., Santoni, A. & Cerboni, C. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Frontiers Immunol. 3, 408 (2012).
  Google Scholar
• Ardolino, M. et al. DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction. Blood 117, 4778–4786 (2011).
  CAS PubMed Google Scholar
• O'Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunol. 7, 507–516 (2006).
  CAS Google Scholar
• Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).
  CAS PubMed PubMed Central Google Scholar
• Paust, S., Senman, B. & von Andrian, U. H. Adaptive immune responses mediated by natural killer cells. Immunol. Rev. 235, 286–296 (2010).
  CAS PubMed PubMed Central Google Scholar
• Foley, B. et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119, 2665–2674 (2012).
  CAS PubMed PubMed Central Google Scholar
• Lopez-Verges, S. et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc. Natl Acad. Sci. USA 108, 14725–14732 (2011).
  CAS PubMed Google Scholar
• Nabekura, T. et al. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40, 225–234 (2014).
  CAS PubMed PubMed Central Google Scholar
• Shibuya, A., Lanier, L. L. & Phillips, J. H. Protein kinase C is involved in the regulation of both signaling and adhesion mediated by DNAX accessory molecule-1 receptor. J. Immunol. 161, 1671–1676 (1998).
  CAS PubMed Google Scholar
• Bryceson, Y. T., March, M. E., Ljunggren, H. G. & Long, E. O. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107, 159–166 (2006).
  CAS PubMed PubMed Central Google Scholar
• Kim, H. S., Das, A., Gross, C. C., Bryceson, Y. T. & Long, E. O. Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity 32, 175–186 (2010).
  CAS PubMed PubMed Central Google Scholar
• Kim, H. S. & Long, E. O. Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells. Sci. Signal. 5, ra49 (2012).
  PubMed Google Scholar
• Rozsnyay, Z. Signaling complex formation of CD44 with src-related kinases. Immunol. Lett. 68, 101–108 (1999).
  CAS PubMed Google Scholar
• Chambers, C. A. The expanding world of co-stimulation: the two-signal model revisited. Trends Immunol. 22, 217–223 (2001).
  CAS PubMed Google Scholar
• Soriani, A. et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503–3511 (2009).
  CAS PubMed Google Scholar
• Carlsten, M. et al. Primary human tumor cells expressing CD155 impair tumor targeting by down-regulating DNAM-1 on NK cells. J. Immunol. 183, 4921–4930 (2009).
  CAS PubMed Google Scholar
• El-Sherbiny, Y. M. et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 67, 8444–8449 (2007).
  CAS PubMed Google Scholar
• Lakshmikanth, T. et al. NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J. Clin. Invest. 119, 1251–1263 (2009).
  CAS PubMed PubMed Central Google Scholar
• Sanchez-Correa, B. et al. Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol. Cell Biol. 90, 109–115 (2012).
  CAS PubMed Google Scholar
• Mamessier, E. et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J. Clin. Invest. 121, 3609–3622 (2011).
  CAS PubMed PubMed Central Google Scholar
• Oshima, T. et al. Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers. Mol. Cancer 12, 60 (2013).
  CAS PubMed PubMed Central Google Scholar
• Iguchi-Manaka, A. et al. Accelerated tumor growth in mice deficient in DNAM-1 receptor. J. Exp. Med. 205, 2959–2964 (2008). This paper, together with reference 7, was the first to show the role of CD226 in NK cell- and CD8+ T cell-mediated tumour immunosurveillance using Cd226 −/− mice.
  CAS PubMed PubMed Central Google Scholar
• Croxford, J. L. et al. ATM-dependent spontaneous regression of early Emu-myc-induced murine B cell leukemia depends on NK and T cells. Blood 121, 2512–2521 (2013).
  CAS PubMed PubMed Central Google Scholar
• Chan, C. J. et al. DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases. J. Immunol. 184, 902–911 (2010).
  CAS PubMed Google Scholar
• Smyth, M. J., Crowe, N. Y. & Godfrey, D. I. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int. Immunol. 13, 459–463 (2001).
  CAS PubMed Google Scholar
• Welch, M. J., Teijaro, J. R., Lewicki, H. A., Colonna, M. & Oldstone, M. B. CD8 T cell defect of TNFα and IL-2 in DNAM-1 deficient mice delays clearance in vivo of a persistent virus infection. Virology 429, 163–170 (2012).
  CAS PubMed PubMed Central Google Scholar
• Magri, G. et al. NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 117, 848–856 (2011).
  CAS PubMed Google Scholar
• Prod'homme, V. et al. Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J. Gen. Virol. 91, 2034–2039 (2010).
  CAS PubMed PubMed Central Google Scholar
• Tomasec, P. et al. Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirus UL141. Nature Immunol. 6, 181–188 (2005).
  CAS Google Scholar
• Matusali, G., Potesta, M., Santoni, A., Cerboni, C. & Doria, M. The human immunodeficiency virus type 1 Nef and Vpu proteins downregulate the natural killer cell-activating ligand PVR. J. Virol. 86, 4496–4504 (2012). References 79–81 show that the downregulation of CD112 and CD155 expression is a common evasion strategy developed by viruses to avoid CD226-mediated NK cell recognition.
  CAS PubMed PubMed Central Google Scholar
• Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).
  CAS PubMed Google Scholar
• Song, G., Bae, S. C., Choi, S., Ji, J. & Lee, Y. Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis. Lupus 21, 1522–1530 (2012).
  PubMed Google Scholar
• Du, Y. et al. Association of the CD226 single nucleotide polymorphism with systemic lupus erythematosus in the Chinese Han population. Tissue Antigens 77, 65–67 (2011).
  CAS PubMed Google Scholar
• Maiti, A. K. et al. Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology 49, 1239–1244 (2010).
  CAS PubMed Google Scholar
• Wieczorek, S. et al. Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener's granulomatosis and confirmation for multiple sclerosis in German patients. Genes Immun. 10, 591–595 (2009).
  CAS PubMed Google Scholar
• Flodstrom-Tullberg, M., Bryceson, Y. T., Shi, F. D., Hoglund, P. & Ljunggren, H. G. Natural killer cells in human autoimmunity. Curr. Opin. Immunol. 21, 634–640 (2009).
  PubMed Google Scholar
• Parham, P. MHC class I molecules and KIRs in human history, health and survival. Nature Rev. Immunol. 5, 201–214 (2005).
  CAS Google Scholar
• Thielens, A., Vivier, E. & Romagne, F. NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Curr. Opin. Immunol. 24, 239–245 (2012).
  CAS PubMed Google Scholar
• Raulet, D. H. & Vance, R. E. Self-tolerance of natural killer cells. Nature Rev. Immunol. 6, 520–531 (2006).
  CAS Google Scholar
• Huse, M., Catherine Milanoski, S. & Abeyweera, T. P. Building tolerance by dismantling synapses: inhibitory receptor signaling in natural killer cells. Immunol. Rev. 251, 143–153 (2013).
  PubMed Google Scholar
• Stebbins, C. C. et al. Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol. Cell. Biol. 23, 6291–6299 (2003).
  CAS PubMed PubMed Central Google Scholar
• Abeyweera, T. P., Merino, E. & Huse, M. Inhibitory signaling blocks activating receptor clustering and induces cytoskeletal retraction in natural killer cells. J. Cell Biol. 192, 675–690 (2011).
  CAS PubMed PubMed Central Google Scholar
• Peterson, M. E. & Long, E. O. Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk. Immunity 29, 578–588 (2008).
  CAS PubMed PubMed Central Google Scholar
• Stewart, C. A. et al. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc. Natl Acad. Sci. USA 102, 13224–13229 (2005).
  CAS PubMed Google Scholar
• Sivori, S. et al. Natural killer cells expressing the KIR2DS1-activating receptor efficiently kill T-cell blasts and dendritic cells: implications in haploidentical HSCT. Blood 117, 4284–4292 (2011).
  CAS PubMed Google Scholar
• Graef, T. et al. KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C. J. Exp. Med. 206, 2557–2572 (2009).
  CAS PubMed PubMed Central Google Scholar
• Rajagopalan, S. & Long, E. O. Understanding how combinations of HLA and KIR genes influence disease. J. Exp. Med. 201, 1025–1029 (2005).
  CAS PubMed PubMed Central Google Scholar
• Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004). This study suggests that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against viral infections.
  CAS PubMed Google Scholar
• Alter, G. et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Exp. Med. 204, 3027–3036 (2007).
  CAS PubMed PubMed Central Google Scholar
• Carr, W. H. et al. Cutting edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. J. Immunol. 178, 647–651 (2007).
  CAS PubMed PubMed Central Google Scholar
• Malnati, M. S. et al. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science 267, 1016–1018 (1995).
  CAS PubMed Google Scholar
• Zappacosta, F., Borrego, F., Brooks, A. G., Parker, K. C. & Coligan, J. E. Peptides isolated from HLA-Cw*0304 confer different degrees of protection from natural killer cell-mediated lysis. Proc. Natl Acad. Sci. USA 94, 6313–6318 (1997).
  CAS PubMed Google Scholar
• Fadda, L. et al. Peptide antagonism as a mechanism for NK cell activation. Proc. Natl Acad. Sci. USA 107, 10160–10165 (2010).
  CAS PubMed Google Scholar
• Rajagopalan, S. & Long, E. O. Antagonizing inhibition gets NK cells going. Proc. Natl Acad. Sci. USA 107, 10333–10334 (2010).
  CAS PubMed Google Scholar
• Alter, G. & Altfeld, M. NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J. Internal Med. 265, 29–42 (2009).
  CAS PubMed Google Scholar
• Katz, G. et al. MHC class I-independent recognition of NK-activating receptor KIR2DS4. J. Immunol. 173, 1819–1825 (2004).
  CAS PubMed Google Scholar
• Brooks, A. G., Posch, P. E., Scorzelli, C. J., Borrego, F. & Coligan, J. E. NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J. Exp. Med. 185, 795–800 (1997).
  CAS PubMed PubMed Central Google Scholar
• Borrego, F., Ulbrecht, M., Weiss, E. H., Coligan, J. E. & Brooks, A. G. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J. Exp. Med. 187, 813–818 (1998).
  CAS PubMed PubMed Central Google Scholar
• Carretero, M. et al. Specific engagement of the CD94/NKG2-A killer inhibitory receptor by the HLA-E class Ib molecule induces SHP-1 phosphatase recruitment to tyrosine-phosphorylated NKG2-A: evidence for receptor function in heterologous transfectants. Eur. J. Immunol. 28, 1280–1291 (1998).
  CAS PubMed Google Scholar
• Lanier, L. L., Corliss, B., Wu, J. & Phillips, J. H. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693–701 (1998).
  CAS PubMed Google Scholar
• Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).
  CAS PubMed Google Scholar
• Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031 (2000).
  CAS PubMed Google Scholar
• Bossard, C. et al. HLA-E/beta2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. Int. J. Cancer 131, 855–863 (2012).
  CAS PubMed Google Scholar
• Kraemer, T., Blasczyk, R. & Bade-Doeding, C. HLA-E: a novel player for histocompatibility. J. Immunol. Res. 2014, 352160 (2014).
  PubMed PubMed Central Google Scholar
• Vance, R. E., Kraft, J. R., Altman, J. D., Jensen, P. E. & Raulet, D. H. Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1(b). J. Exp. Med. 188, 1841–1848 (1998).
  CAS PubMed PubMed Central Google Scholar
• Orr, M. T. et al. Development and function of CD94-deficient natural killer cells. PLoS ONE 5, e15184 (2010).
  CAS PubMed PubMed Central Google Scholar
• Fang, M. et al. CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 34, 579–589 (2011). This study using CD94-deficient mice shows that the activating receptor formed by CD94 and NKG2E is essential for the resistance of C57BL/6 mice to mousepox.
  CAS PubMed PubMed Central Google Scholar
• Guma, M. et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104, 3664–3671 (2004).
  CAS PubMed Google Scholar
• Beziat, V. et al. CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur. J. Immunol. 42, 447–457 (2012).
  CAS PubMed Google Scholar
• Guma, M. et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 107, 3624–3631 (2006).
  CAS PubMed Google Scholar
• Lopez-Botet, M., Muntasell, A. & Vilches, C. The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection. Semin. Immunol. 26, 145–151 (2014).
  CAS PubMed Google Scholar
• Kim, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005).
  CAS PubMed Google Scholar
• Anfossi, N. et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342 (2006).
  CAS PubMed Google Scholar
• Viant, C. et al. SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Nature Commun. 5, 5108 (2014).
  CAS Google Scholar
• Elliott, J. M. & Yokoyama, W. M. Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol. 32, 364–372 (2011).
  CAS PubMed PubMed Central Google Scholar
• Tripathy, S. K. et al. Continuous engagement of a self-specific activation receptor induces NK cell tolerance. J. Exp. Med. 205, 1829–1841 (2008).
  CAS PubMed PubMed Central Google Scholar
• Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity? Nature Rev. Immunol. 13, 764–769 (2013). This is an outstanding review on the formulation of a new immune paradigm 'the discontinuity theory'.
  CAS Google Scholar
• Seth, S. et al. Intranodal interaction with dendritic cells dynamically regulates surface expression of the co-stimulatory receptor CD226 protein on murine T cells. J. Biol. Chem. 286, 39153–39163 (2011).
  CAS PubMed PubMed Central Google Scholar
• Callahan, M. K. & Wolchok, J. D. At the Bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J. Leukoc. Biol. 94, 41–53 (2013).
  CAS PubMed PubMed Central Google Scholar
• Koyama, M. et al. Promoting regulation via the inhibition of DNAM-1 after transplantation. Blood 121, 3511–3520 (2013).
  CAS PubMed Google Scholar
• Takai, Y., Miyoshi, J., Ikeda, W. & Ogita, H. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nature Rev. Mol. Cell Biol. 9, 603–615 (2008).
  CAS Google Scholar
• Erickson, B. M., Thompson, N. L. & Hixson, D. C. Tightly regulated induction of the adhesion molecule necl-5/CD155 during rat liver regeneration and acute liver injury. Hepatology 43, 325–334 (2006).
  CAS PubMed Google Scholar
• Hirota, T., Irie, K., Okamoto, R., Ikeda, W. & Takai, Y. Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf–MEK–ERK–AP-1 pathway. Oncogene 24, 2229–2235 (2005).
  CAS PubMed Google Scholar
• Sloan, K. E. et al. CD155/PVR plays a key role in cell motility during tumor cell invasion and migration. BMC Cancer 4, 73 (2004).
  PubMed PubMed Central Google Scholar
• Tane, S. et al. The role of Necl-5 in the invasive activity of lung adenocarcinoma. Exp. Mol. Pathol. 94, 330–335 (2013).
  CAS PubMed Google Scholar
• Nakai, R. et al. Overexpression of Necl-5 correlates with unfavorable prognosis in patients with lung adenocarcinoma. Cancer Sci. 101, 1326–1330 (2010).
  CAS PubMed Google Scholar
• Morimoto, K. et al. Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs. Oncogene 27, 264–273 (2008).
  CAS PubMed Google Scholar
• Vassena, L., Giuliani, E., Matusali, G., Cohen, E. & Doria, M. The human immunodeficiency virus type 1 Vpr protein upregulates PVR via activation of the ATR-mediated DNA damage response pathway. J. General Virol. 94, 2664–2669 (2013).
  CAS Google Scholar
• Cerboni, C. et al. The DNA damage response: a common pathway in the regulation of NKG2D and DNAM-1 ligand expression in normal, infected, and cancer cells. Front. Immunol. 4, 508 (2014).
  PubMed PubMed Central Google Scholar
• Kennedy, J. et al. A molecular analysis of NKT cells: identification of a class-I restricted T cell-associated molecule (CRTAM). J. Leukoc. Biol. 67, 725–734 (2000).
  CAS PubMed Google Scholar
• Arase, N. et al. Heterotypic interaction of CRTAM with Necl2 induces cell adhesion on activated NK cells and CD8+ T cells. Int. Immunol. 17, 1227–1237 (2005).
  CAS PubMed Google Scholar
• Boles, K. S., Barchet, W., Diacovo, T., Cella, M. & Colonna, M. The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM. Blood 106, 779–786 (2005).
  CAS PubMed Google Scholar
• Takeuchi, A. et al. CRTAM confers late-stage activation of CD8+ T cells to regulate retention within lymph node. J. Immunol. 183, 4220–4228 (2009).
  CAS PubMed Google Scholar
• Yeh, J. H., Sidhu, S. S. & Chan, A. C. Regulation of a late phase of T cell polarity and effector functions by Crtam. Cell 132, 846–859 (2008). This article provides an in-depth analysis of the role and signalling of CRTAM in CD4+ T cells using CRTAM-deficient mice.
  CAS PubMed Google Scholar
• Ikeda, W. et al. Nectin-like molecule-5/Tage4 enhances cell migration in an integrin-dependent, Nectin-3-independent manner. J. Biol. Chem. 279, 18015–18025 (2004).
  CAS PubMed Google Scholar
• Freistadt, M. S. & Eberle, K. E. Physical association between CD155 and CD44 in human monocytes. Mol. Immunol. 34, 1247–1257 (1997).
  CAS PubMed Google Scholar
• Mueller, S. & Wimmer, E. Recruitment of nectin-3 to cell-cell junctions through _trans_-heterophilic interaction with CD155, a vitronectin and poliovirus receptor that localizes to αvβ3 integrin-containing membrane microdomains. J. Biol. Chem. 278, 31251–31260 (2003).
  CAS PubMed Google Scholar