Zwirner, N.W.; Ziblat, A."Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: The case of IL-27" (2017) Frontiers in Immunology. 8(JAN)
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Natural killer (NK) cells are characterized by their ability to detect and induce apoptosis of susceptible target cells and by secretion of immunoregulatory cytokines such as IFN-γ. Activation of these effector functions is triggered upon recognition of tumor and pathogen (mostly virus)-infected cells and because of a bidirectional cross talk that NK cells establish with other cells of myeloid origin such as dendritic cells (DC) and macrophages. A common characteristic of these myeloid cells is their ability to secrete different members of the IL-12 family of cytokines such as IL-12, IL-23, and IL-27 and cytokines such as IL-15 and IL-18. Although the effect of IL-12, IL-15, and IL-18 has been characterized, the effect of IL-23 and IL-27 on NK cells (especially human) remains ill-defined. Particularly, IL-27 is a cytokine with dual functions as it has been described as pro- and as anti-inflammatory in different experimental settings. Recent evidence indicates that this cytokine indeed promotes human NK cell activation, IFN-γ secretion, NKp46-dependent NK cell-mediated cytotoxicity, and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC) against monoclonal Ab-coated tumor cells. Remarkably, IL-27 also primes NK cells for IL-18 responsiveness, enhancing these functional responses. Consequently, IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions, which likely contributes to foster the adaptive immune response in different physiopathological conditions. © 2017 Zwirner and Ziblat.


Documento: Artículo
Título:Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: The case of IL-27
Autor:Zwirner, N.W.; Ziblat, A.
Filiación:Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME CONICET), Ciudad de Buenos Aires, Argentina
Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina
Palabras clave:Cytokines; Cytotoxicity; Dendritic cells; Immunologic; Innate immunity; NK cells; cetuximab; gamma interferon; interleukin 12; interleukin 18; interleukin 23; interleukin 27; rituximab; STAT1 protein; STAT3 protein; trastuzumab; adaptive immunity; antibody dependent cellular cytotoxicity; apoptosis; bone marrow cell; CD4+ T lymphocyte; cell function; cell stimulation; dendritic cell; gene expression; human; immunoregulation; immunosurveillance; immunotherapy; inflammation; innate immunity; lymphocyte activation; macrophage; molecular interaction; natural killer cell; natural killer cell mediated cytotoxicity; nonhuman; Short Survey; tissue injury; upregulation
Título revista:Frontiers in Immunology
Título revista abreviado:Front. Immunol.
CAS:cetuximab, 205923-56-4; gamma interferon, 82115-62-6; interleukin 12, 138415-13-1; interleukin 18, 189304-55-0; rituximab, 174722-31-7; trastuzumab, 180288-69-1, 1446410-98-5


  • Newman, K.C., Riley, E.M., Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens (2007) Nat Rev Immunol, 7 (4), pp. 279-291
  • Lanier, L.L., Up on the tightrope: natural killer cell activation and inhibition (2008) Nat Immunol, 9 (5), pp. 495-502
  • Orange, J.S., Brodeur, S.R., Jain, A., Bonilla, F.A., Schneider, L.C., Kretschmer, R., Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations (2002) J Clin Invest, 109 (11), pp. 1501-1509
  • Orange, J.S., Unraveling human natural killer cell deficiency (2012) J Clin Invest, 122 (3), pp. 798-801
  • Carrega, P., Ferlazzo, G., Natural killer cell distribution and trafficking in human tissues (2012) Front Immunol, 3, p. 347
  • Melsen, J.E., Lugthart, G., Lankester, A.C., Schilham, M.V., Human circulating and tissue-resident CD56(bright) natural killer cell populations (2016) Front Immunol, 7, p. 262
  • Morvan, M.G., Lanier, L.L., NK cells and cancer: you can teach innate cells new tricks (2016) Nat Rev Cancer, 16 (1), pp. 7-19
  • Geiger, T.L., Sun, J.C., Development and maturation of natural killer cells (2016) Curr Opin Immunol, 39, pp. 82-89
  • Moretta, A., Natural killer cells and dendritic cells: rendezvous in abused tissues (2002) Nat Rev Immunol, 2 (12), pp. 957-964
  • Moretta, A., Marcenaro, E., Parolini, S., Ferlazzo, G., Moretta, L., NK cells at the interface between innate and adaptive immunity (2008) Cell Death Differ, 15 (2), pp. 226-233
  • Caligiuri, M.A., Human natural killer cells (2008) Blood, 112 (3), pp. 461-469
  • Strowig, T., Brilot, F., Munz, C., Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity (2008) J Immunol, 180 (12), pp. 7785-7791
  • Ferlazzo, G., Pack, M., Thomas, D., Paludan, C., Schmid, D., Strowig, T., Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs (2004) Proc Natl Acad Sci U S A, 101 (47), pp. 16606-16611
  • Ferlazzo, G., Thomas, D., Lin, S.L., Goodman, K., Morandi, B., Muller, W.A., The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic (2004) J Immunol, 172 (3), pp. 1455-1462
  • Chan, A., Hong, D.L., Atzberger, A., Kollnberger, S., Filer, A.D., Buckley, C.D., CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts (2007) J Immunol, 179 (1), pp. 89-94
  • Romagnani, C., Juelke, K., Falco, M., Morandi, B., D'Agostino, A., Costa, R., CD56brightCD16-killer Ig-like receptor-NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation (2007) J Immunol, 178 (8), pp. 4947-4955
  • Luetke-Eversloh, M., Killig, M., Romagnani, C., Signatures of human NK cell development and terminal differentiation (2013) Front Immunol, 4, p. 499
  • Campbell, J.J., Qin, S., Unutmaz, D., Soler, D., Murphy, K.E., Hodge, M.R., Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire (2001) J Immunol, 166 (11), pp. 6477-6482
  • Cella, M., Miller, H., Song, C., Beyond NK cells: the expanding universe of innate lymphoid cells (2014) Front Immunol, 5, p. 282
  • Spits, H., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J.P., Eberl, G., Innate lymphoid cells - a proposal for uniform nomenclature (2013) Nat Rev Immunol, 13 (2), pp. 145-149
  • McKenzie, A.N., Spits, H., Eberl, G., Innate lymphoid cells in inflammation and immunity (2014) Immunity, 41 (3), pp. 366-374
  • Diefenbach, A., Colonna, M., Koyasu, S., Development, differentiation, and diversity of innate lymphoid cells (2014) Immunity, 41 (3), pp. 354-365
  • Bartel, Y., Bauer, B., Steinle, A., Modulation of NK cell function by genetically coupled C-type lectin-like receptor/ligand pairs encoded in the human natural killer gene complex (2013) Front Immunol, 4, p. 362
  • Zwirner, N.W., Domaica, C.I., Cytokine regulation of natural killer cell effector functions (2010) Biofactors, 36 (4), pp. 274-288
  • Girart, M.V., Fuertes, M.B., Domaica, C.I., Rossi, L.E., Zwirner, N.W., Engagement of TLR3, TLR7, and NKG2D regulate IFN-gamma secretion but not NKG2D-mediated cytotoxicity by human NK cells stimulated with suboptimal doses of IL-12 (2007) J Immunol, 179 (6), pp. 3472-3479
  • Chalifour, A., Jeannin, P., Gauchat, J.F., Blaecke, A., Malissard, M., N'Guyen, T., Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production (2004) Blood, 104 (6), pp. 1778-1783
  • Hart, O.M., Athie-Morales, V., O'Connor, G.M., Gardiner, C.M., TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production (2005) J Immunol, 175 (3), pp. 1636-1642
  • Sivori, S., Falco, M., Della Chiesa, M., Carlomagno, S., Vitale, M., Moretta, L., CpG and double-stranded RNA trigger human NK cells by toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells (2004) Proc Natl Acad Sci U S A, 101 (27), pp. 10116-10121
  • Gorski, K.S., Waller, E.L., Bjornton-Severson, J., Hanten, J.A., Riter, C.L., Kieper, W.C., Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists (2006) Int Immunol, 18 (7), pp. 1115-1126
  • Schmidt, K.N., Leung, B., Kwong, M., Zarember, K.A., Satyal, S., Navas, T.A., APC-independent activation of NK cells by the toll-like receptor 3 agonist double-stranded RNA (2004) J Immunol, 172 (1), pp. 138-143
  • Ferlazzo, G., Tsang, M.L., Moretta, L., Melioli, G., Steinman, R.M., Munz, C., Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells (2002) J Exp Med, 195 (3), pp. 343-351
  • Pende, D., Castriconi, R., Romagnani, P., Spaggiari, G.M., Marcenaro, S., Dondero, A., Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction (2006) Blood, 107 (5), pp. 2030-2036
  • Martin-Fontecha, A., Thomsen, L.L., Brett, S., Gerard, C., Lipp, M., Lanzavecchia, A., Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming (2004) Nat Immunol, 5 (12), pp. 1260-1265
  • Spaggiari, G.M., Carosio, R., Pende, D., Marcenaro, S., Rivera, P., Zocchi, M.R., NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46 (2001) Eur J Immunol, 31 (6), pp. 1656-1665
  • Walzer, T., Dalod, M., Robbins, S.H., Zitvogel, L., Vivier, E., Natural-killer cells and dendritic cells: "l'union fait la force" (2005) Blood, 106 (7), pp. 2252-2258
  • Vignali, D.A., Kuchroo, V.K., IL-12 family cytokines: immunological playmakers (2012) Nat Immunol, 13 (8), pp. 722-728
  • Seder, R.A., Gazzinelli, R., Sher, A., Paul, W.E., Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming (1993) Proc Natl Acad Sci U S A, 90 (21), pp. 10188-10192
  • Gazzinelli, R.T., Hieny, S., Wynn, T.A., Wolf, S., Sher, A., Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts (1993) Proc Natl Acad Sci U S A, 90 (13), pp. 6115-6119
  • Gazzinelli, R.T., Wysocka, M., Hayashi, S., Denkers, E.Y., Hieny, S., Caspar, P., Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii (1994) J Immunol, 153 (6), pp. 2533-2543
  • Jacobson, N.G., Szabo, S.J., Weber-Nordt, R.M., Zhong, Z., Schreiber, R.D., Darnell, J.E., Jr., Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4 (1995) J Exp Med, 181 (5), pp. 1755-1762
  • Thierfelder, W.E., van Deursen, J.M., Yamamoto, K., Tripp, R.A., Sarawar, S.R., Carson, R.T., Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells (1996) Nature, 382 (6587), pp. 171-174
  • Kaplan, M.H., Sun, Y.L., Hoey, T., Grusby, M.J., Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice (1996) Nature, 382 (6587), pp. 174-177
  • Szabo, S.J., Dighe, A.S., Gubler, U., Murphy, K.M., Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells (1997) J Exp Med, 185 (5), pp. 817-824
  • Nguyen, K.B., Salazar-Mather, T.P., Dalod, M.Y., Van Deusen, J.B., Wei, X.Q., Liew, F.Y., Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection (2002) J Immunol, 169 (8), pp. 4279-4287
  • Andoniou, C.E., van Dommelen, S.L., Voigt, V., Andrews, D.M., Brizard, G., Asselin-Paturel, C., Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity (2005) Nat Immunol, 6 (10), pp. 1011-1019
  • Loza, M.J., Perussia, B., The IL-12 signature: NK cell terminal CD56+high stage and effector functions (2004) J Immunol, 172 (1), pp. 88-96
  • Hashimoto, W., Osaki, T., Okamura, H., Robbins, P.D., Kurimoto, M., Nagata, S., Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand-and perforin-induced tumor apoptosis, respectively (1999) J Immunol, 163 (2), pp. 583-589
  • Kodama, T., Takeda, K., Shimozato, O., Hayakawa, Y., Atsuta, M., Kobayashi, K., Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12 (1999) Eur J Immunol, 29 (4), pp. 1390-1396
  • Orange, J.S., Wang, B., Terhorst, C., Biron, C.A., Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration (1995) J Exp Med, 182 (4), pp. 1045-1056
  • Cooper, M.A., Elliott, J.M., Keyel, P.A., Yang, L., Carrero, J.A., Yokoyama, W.M., Cytokine-induced memory-like natural killer cells (2009) Proc Natl Acad Sci U S A, 106 (6), pp. 1915-1919
  • O'Sullivan, T.E., Sun, J.C., Lanier, L.L., Natural killer cell memory (2015) Immunity, 43 (4), pp. 634-645
  • Yang, J., Kawamura, I., Zhu, H., Mitsuyama, M., Involvement of natural killer cells in nitric oxide production by spleen cells after stimulation with Mycobacterium bovis BCG. Study of the mechanism of the different abilities of viable and killed BCG (1995) J Immunol, 155 (12), pp. 5728-5735
  • Mailliard, R.B., Son, Y.I., Redlinger, R., Coates, P.T., Giermasz, A., Morel, P.A., Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function (2003) J Immunol, 171 (5), pp. 2366-2373
  • Kastelein, R.A., Hunter, C.A., Cua, D.J., Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation (2007) Annu Rev Immunol, 25, pp. 221-242
  • Pflanz, S., Timans, J.C., Cheung, J., Rosales, R., Kanzler, H., Gilbert, J., IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells (2002) Immunity, 16 (6), pp. 779-790
  • de Groot, R., van Beelen, A.J., Bakdash, G., Taanman-Kueter, E.W., de Jong, E.C., Kapsenberg, M.L., Viral dsRNA-activated human dendritic cells produce IL-27, which selectively promotes cytotoxicity in naive CD8+ T cells (2012) J Leukoc Biol, 92 (3), pp. 605-610
  • Molle, C., Nguyen, M., Flamand, V., Renneson, J., Trottein, F., De Wit, D., IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3 (2007) J Immunol, 178 (12), pp. 7607-7615
  • Iyer, S.S., Ghaffari, A.A., Cheng, G., Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages (2010) J Immunol, 185 (11), pp. 6599-6607
  • Pirhonen, J., Siren, J., Julkunen, I., Matikainen, S., IFN-alpha regulates toll-like receptor-mediated IL-27 gene expression in human macrophages (2007) J Leukoc Biol, 82 (5), pp. 1185-1192
  • Parham, C., Chirica, M., Timans, J., Vaisberg, E., Travis, M., Cheung, J., A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R (2002) J Immunol, 168 (11), pp. 5699-5708
  • Hu, J., Yuan, X., Belladonna, M.L., Ong, J.M., Wachsmann-Hogiu, S., Farkas, D.L., Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells (2006) Cancer Res, 66 (17), pp. 8887-8896
  • Kaiga, T., Sato, M., Kaneda, H., Iwakura, Y., Takayama, T., Tahara, H., Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12 (2007) J Immunol, 178 (12), pp. 7571-7580
  • Hu, P., Hu, H.D., Chen, M., Peng, M.L., Tang, L., Tang, K.F., Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma (2009) Mol Immunol, 46 (8-9), pp. 1654-1662
  • Lo, C.H., Lee, S.C., Wu, P.Y., Pan, W.Y., Su, J., Cheng, C.W., Antitumor and antimetastatic activity of IL-23 (2003) J Immunol, 171 (2), pp. 600-607
  • Yoshida, H., Hunter, C.A., The immunobiology of interleukin-27 (2015) Annu Rev Immunol, 33, pp. 417-443
  • Aparicio-Siegmund, S., Garbers, C., The biology of interleukin-27 reveals unique pro-and anti-inflammatory functions in immunity (2015) Cytokine Growth Factor Rev, 26 (5), pp. 579-586
  • Takeda, A., Hamano, S., Yamanaka, A., Hanada, T., Ishibashi, T., Mak, T.W., Role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment (2003) J Immunol, 170 (10), pp. 4886-4890
  • Lucas, S., Ghilardi, N., Li, J., de Sauvage, F.J., IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and-independent mechanisms (2003) Proc Natl Acad Sci U S A, 100 (25), pp. 15047-15052
  • Hibbert, L., Pflanz, S., De Waal Malefyt, R., Kastelein, R.A., IL-27 and IFN-alpha signal via Stat1 and Stat3 and induce T-Bet and IL-12Rbeta2 in naive T cells (2003) J Interferon Cytokine Res, 23 (9), pp. 513-522
  • Wei, J., Xia, S., Sun, H., Zhang, S., Wang, J., Zhao, H., Critical role of dendritic cell-derived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells (2013) J Immunol, 191 (1), pp. 500-508
  • Oniki, S., Nagai, H., Horikawa, T., Furukawa, J., Belladonna, M.L., Yoshimoto, T., Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma (2006) Cancer Res, 66 (12), pp. 6395-6404
  • Chiyo, M., Shimozato, O., Yu, L., Kawamura, K., Iizasa, T., Fujisawa, T., Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals (2005) Int J Cancer, 115 (3), pp. 437-442
  • Cocco, C., Pistoia, V., Airoldi, I., Anti-leukemic properties of IL-12, IL-23 and IL-27: differences and similarities in the control of pediatric B acute lymphoblastic leukemia (2012) Crit Rev Oncol Hematol, 83 (3), pp. 310-318
  • Liu, L., Wang, S., Shan, B., Shao, L., Sato, A., Kawamura, K., IL-27-mediated activation of natural killer cells and inflammation produced antitumour effects for human oesophageal carcinoma cells (2008) Scand J Immunol, 68 (1), pp. 22-29
  • Liu, Z., Liu, J.Q., Talebian, F., Wu, L.C., Li, S., Bai, X.F., IL-27 enhances the survival of tumor antigen-specific CD8+ T cells and programs them into IL-10-producing, memory precursor-like effector cells (2013) Eur J Immunol, 43 (2), pp. 468-479
  • Matsui, M., Kishida, T., Nakano, H., Yoshimoto, K., Shin-Ya, M., Shimada, T., Interleukin-27 activates natural killer cells and suppresses NK-resistant head and neck squamous cell carcinoma through inducing antibody-dependent cellular cytotoxicity (2009) Cancer Res, 69 (6), pp. 2523-2530
  • Salcedo, R., Stauffer, J.K., Lincoln, E., Back, T.C., Hixon, J.A., Hahn, C., IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: role for CD8+ T cells (2004) J Immunol, 173 (12), pp. 7170-7182
  • Laroni, A., Gandhi, R., Beynon, V., Weiner, H.L., IL-27 imparts immunoregulatory function to human NK cell subsets (2011) PLoS One, 6 (10)
  • Ziblat, A., Domaica, C.I., Spallanzani, R.G., Iraolagoitia, X.L., Rossi, L.E., Avila, D.E., IL-27 stimulates human NK-cell effector functions and primes NK cells for IL-18 responsiveness (2015) Eur J Immunol, 45 (1), pp. 192-202
  • Ross, M.E., Caligiuri, M.A., Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response (1997) Blood, 89 (3), pp. 910-918
  • Fehniger, T.A., Shah, M.H., Turner, M.J., VanDeusen, J.B., Whitman, S.P., Cooper, M.A., Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response (1999) J Immunol, 162 (8), pp. 4511-4520
  • Fehniger, T.A., Cooper, M.A., Nuovo, G.J., Cella, M., Facchetti, F., Colonna, M., CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity (2003) Blood, 101 (8), pp. 3052-3057
  • Carson, W.E., Dierksheide, J.E., Jabbour, S., Anghelina, M., Bouchard, P., Ku, G., Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction (2000) Blood, 96 (4), pp. 1465-1473
  • Smyth, M.J., Swann, J., Kelly, J.M., Cretney, E., Yokoyama, W.M., Diefenbach, A., NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer (2004) J Exp Med, 200 (10), pp. 1325-1335
  • Lauwerys, B.R., Renauld, J.C., Houssiau, F.A., Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18 (1999) Cytokine, 11 (11), pp. 822-830
  • Fabbi, M., Carbotti, G., Ferrini, S., Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP (2015) J Leukoc Biol, 97 (4), pp. 665-675
  • Kalinski, P., Giermasz, A., Nakamura, Y., Basse, P., Storkus, W.J., Kirkwood, J.M., Helper role of NK cells during the induction of anticancer responses by dendritic cells (2005) Mol Immunol, 42 (4), pp. 535-539
  • Wong, J.L., Berk, E., Edwards, R.P., Kalinski, P., IL-18-primed helper NK cells collaborate with dendritic cells to promote recruitment of effector CD8+ T cells to the tumor microenvironment (2013) Cancer Res, 73 (15), pp. 4653-4662
  • Takeda, K., Tsutsui, H., Yoshimoto, T., Adachi, O., Yoshida, N., Kishimoto, T., Defective NK cell activity and Th1 response in IL-18-deficient mice (1998) Immunity, 8 (3), pp. 383-390
  • Chaix, J., Tessmer, M.S., Hoebe, K., Fuseri, N., Ryffel, B., Dalod, M., Priming of NK cells by IL-18 (2008) J Immunol, 181 (3), pp. 1627-1631
  • Semino, C., Angelini, G., Poggi, A., Rubartelli, A., NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1 (2005) Blood, 106 (2), pp. 609-616
  • Szabo, S.J., Sullivan, B.M., Stemmann, C., Satoskar, A.R., Sleckman, B.P., Glimcher, L.H., Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells (2002) Science, 295 (5553), pp. 338-342
  • Yu, J., Wei, M., Boyd, Z., Lehmann, E.B., Trotta, R., Mao, H., Transcriptional control of human T-BET expression: the role of Sp1 (2007) Eur J Immunol, 37 (9), pp. 2549-2561
  • Matsuda, J.L., George, T.C., Hagman, J., Gapin, L., Temporal dissection of T-bet functions (2007) J Immunol, 178 (6), pp. 3457-3465
  • Wang, R., Jaw, J.J., Stutzman, N.C., Zou, Z., Sun, P.D., Natural killer cell-produced IFN-gamma and TNF-alpha induce target cell cytolysis through up-regulation of ICAM-1 (2012) J Leukoc Biol, 91 (2), pp. 299-309
  • Mullen, A.C., High, F.A., Hutchins, A.S., Lee, H.W., Villarino, A.V., Livingston, D.M., Role of T-bet in commitment of TH1 cells before IL-12-dependent selection (2001) Science, 292 (5523), pp. 1907-1910
  • Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells (2002) Nat Immunol, 3 (6), pp. 549-557


---------- APA ----------
Zwirner, N.W. & Ziblat, A. (2017) . Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: The case of IL-27. Frontiers in Immunology, 8(JAN).
---------- CHICAGO ----------
Zwirner, N.W., Ziblat, A. "Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: The case of IL-27" . Frontiers in Immunology 8, no. JAN (2017).
---------- MLA ----------
Zwirner, N.W., Ziblat, A. "Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: The case of IL-27" . Frontiers in Immunology, vol. 8, no. JAN, 2017.
---------- VANCOUVER ----------
Zwirner, N.W., Ziblat, A. Regulation of NK cell activation and effector functions by the IL-12 family of cytokines: The case of IL-27. Front. Immunol. 2017;8(JAN).