In Vivo DC Editing by NK Cells Statistical Analysis The statistical significance of differences was evaluated with Student’s t test or Mann Whitney test using Prism Graphpad software (GraphPad Software Inc., La Jolla, CA). All error bars represent SEM. Author Contributions Conceived and designed the experiments: BM GF. Performed the experiments: BM L. Mortara LC. Analyzed the data: BM L. Mortara LC RSA L. Moretta AM MCM GF. Contributed reagents/materials/ analysis tools: GF L. Moretta MCM . Wrote the paper: BM LC GF AM. References 1. Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47: 187–376. 2. Moretta L, Ciccone E, Moretta A, Hoglund P, Ohlen C, et al. (1992) Allorecognition by NK cells: nonself or no self? Immunol Today 13: 300–306. 3. Moretta L, Ciccone E, Mingari MC, Biassoni R, Moretta A (1994) Human natural killer cells: origin, clonality, specificity, and receptors. Adv Immunol 55: 341–380. 4. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, et al. (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97: 3146–3151. 5. Ferlazzo G, Thomas D, Lin SL, Goodman K, Morandi B, et al. (2004) The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol 172: 1455– 1462. 6. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, et al. (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331: 44–49. 7. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, et al. (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19: 197–223. 8. Yokoyama WM, Seaman WE (1993) The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu Rev Immunol 11: 613–635. 9. Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, et al. (1996) Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 14: 619–648. 10. Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16: 359–393. 11. Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17: 875–904. 12. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, et al. (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5: 405–411. 13. Piccioli D, Sbrana S, Melandri E, Valiante NM (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 195: 335–341. 14. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, et al. (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195: 327–333. 15. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, et al. (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195: 343–351. 16. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA (2004) NK cell and DC interactions. Trends Immunol 25: 47–52. 17. Andoniou CE, van Dommelen SL, Voigt V, Andrews DM, Brizard G, et al. (2005) Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat Immunol 6: 1011– 101 18. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, et al. (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5: 1260–1265. 19. Morandi B, Bougras G, Muller WA, Ferlazzo G, Munz C (2006) NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-gamma secretion. Eur J Immunol 36: 2394–2400. 20. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, et al. (2004) Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci U S A 101: 16606–16611. 21. Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H, et al. (2003) Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19: 561–569 22. Pende D, Castriconi R, Romagnani P, Spaggiari GM, Marcenaro S, et al. (2006) 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. 23. Della Chiesa M, Vitale M, Carlomagno S, Ferlazzo G, Moretta L, et al. (2003) The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors. Eur J Immunol 33: 1657–1666. 24. Ferlazzo G (2005) Natural killer and dendritic cell liaison: recent insights and open questions. Immunol Lett 101: 12–17. 25. Moretta A, Marcenaro E, Sivori S, Della Chiesa M, Vitale M, et al. (2005) Early liaisons between cells of the innate immune system in inflamed peripheral tissues. Trends Immunol 26: 668–6675. 26. Moretta A (2002) Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2: 957–964. 27. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E (2005) Natural-killer cells and dendritic cells: ‘‘l’union fait la force’’. Blood 106: 2252–2258. 28. Ferlazzo G, Munz C (2004) NK cell compartments and their activation by dendritic cells. J Immunol 172: 1333–1339. 29. Hayakawa Y, Screpanti V, Yagita H, Grandien A, Ljunggren HG, et al. (2004) NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J Immunol 172: 123–129. 30. Melki MT, Saidi H, Dufour A, Olivo-Marin JC, Gougeon ML (2010) Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk–a pivotal role of HMGB1. PLoS Pathog 6: e1000862. 31. Persson CM, Assarsson E, Vahlne G, Brodin P, Chambers BJ (2008) Critical role of Qa1b in the protection of mature dendritic cells from NK cell-mediated killing. Scand J Immunol 67: 30–36. 32. Laffont S, Seillet C, Ortaldo J, Coudert JD, Guery JC (2008) Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells. Blood 112: 661– 671. 33. Alter G, Kavanagh D, Rihn S, Luteijn R, Brooks D, et al. (2010) IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection. J Clin Invest 120: 1905–1913. 34. Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, et al. (2010) Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 207: 1333–1343. 35. Adam C, King S, Allgeier T, Braumuller H, Luking C, et al. (2005) DC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction. Blood 106: 338–344. 36. Nanni P, de Giovanni C, Lollini PL, Nicoletti G, Prodi G (1983) TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma. Clin Exp Metastasis 1: 373–380. 37. Huang AY, Gulden PH, Woods AS, Thomas MC, Tong CD, et al. (1996) The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. Proc Natl Acad Sci U S A 93: 9730–9735. 38. Romagnani C, Juelke K, Falco M, Morandi B, D’Agostino A, et al. (2010) CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation. Blood1 16(8): 1299– 1307. 39. Mailliard RB, Alber SM, Shen H, Watkins SC, Kirkwood JM, et al. (2005) IL- 18-induced CD83+CCR7+ NK helper cells. J Exp Med 202(7): 941–953. 40. Marcenaro E, Cantoni C, Pesce S, Prato C, Pende D, et al. (2009) Uptake of CCR7 and acquisition of migratory properties by human KIR+ NK cells interacting with monocyte-derived DC or EBV cell lines: regulation by KIR/ HLA-class I interaction. Blood 114(19): 4108–4116. 41. Bellora F, Castriconi R, Dondero A, Reggiardo G, Moretta L, et al. (2010) The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proc Natl Acad Sci U S A 107(50): 21659–21664. 42. Kiessling R, Klein E, Wigzell H (1975) ‘‘Natural’’ killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur.J.Immunol. 5(2): 112–117, 1975. 43. Mortara L, Castellani P, Meazza R, Tosi G, De Lerma Barbaro A, et al. (2006) CIITA-induced MHC class II expression in mammary adenocarcinoma leads to a Th1 polarization of the tumor microenvironment, tumor rejection, and specific antitumor memory. Clin Cancer Res 12: 3435–3443. PLoS ONE | www.plosone.org 7 June 2012 | Volume 7 | Issue 6 | e39170