Dendritic cells play a central role in keeping the balance between immunity and immune tolerance. A key factor in this equilibrium is the lifespan of DC, as its reduction restrains antigen availability leading to termination of immune responses. Here we show that lipopolysaccharide-driven DC maturation is paralleled by increased nuclear levels of p50 NF-κB, an event associated with DC apoptosis. Lack of p50 in murine DC promoted increased lifespan, enhanced level of maturation associated with increased expression of the proinflammatory cytokines IL-1, IL-18 and IFN-β, enhanced capacity of activating and expanding CD4+ and CD8+ T cells in vivo and decreased ability to induce differentiation of FoxP3+ regulatory T cells. In agreement, vaccination of melanoma-bearing mice with antigen-pulsed LPS-treated p50？/？ BM-DC boosted antitumor immunity and inhibition of tumor growth. We propose that nuclear accumulation of the p50 NF-κB subunit in DC, as occurring during lipopolysaccharide-driven maturation, is a homeostatic mechanism tuning the balance between uncontrolled activation of adaptive immunity and immune tolerance.
References
[1]
Steinman RM, Hawiger D, Liu K, Bonifaz L, Bonnyay D, et al. (2003) Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann N Y Acad Sci 987: 15–25.
[2]
Banchereau J, Paczesny S, Blanco P, Bennett L, Pascual V, et al. (2003) Dendritic cells: controllers of the immune system and a new promise for immunotherapy. Ann N Y Acad Sci 987: 180–187.
[3]
Lanzavecchia A, Sallusto F (2004) Lead and follow: the dance of the dendritic cell and T cell. Nat Immunol 5: 1201–1202.
[4]
Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2: 675–680.
[5]
Reis e Sousa C (2006) Dendritic cells in a mature age. Nat Rev Immunol 6: 476–483.
[6]
De Gregorio E, D’Oro U, Wack A (2009) Immunology of TLR-independent vaccine adjuvants. Curr Opin Immunol 21: 339–345.
Melief CJ (2008) Cancer immunotherapy by dendritic cells. Immunity 29: 372–383.
[9]
Palucka K, Ueno H, Banchereau J (2011) Recent developments in cancer vaccines. J Immunol 186: 1325–1331.
[10]
Zanoni I, Granucci F (2011) The regulatory role of dendritic cells in the induction and maintenance of T-cell tolerance. Autoimmunity 44: 23–32.
[11]
Dai J, Liu B, Cua DJ, Li Z (2007) Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. Eur J Immunol 37: 706–715.
[12]
Grohmann U, Fallarino F, Puccetti P (2003) Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 24: 242–248.
[13]
Fallarino F, Grohmann U (2011) Using an ancient tool for igniting and propagating immune tolerance: IDO as an inducer and amplifier of regulatory T cell functions. Curr Med Chem 18: 2215–2221.
[14]
Zanoni I, Ostuni R, Capuano G, Collini M, Caccia M, et al. (2009) CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature 460: 264–268.
[15]
Hou WS, Van Parijs L (2004) A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells. Nat Immunol 5: 583–589.
[16]
Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13: 816–825.
[17]
Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P (1998) Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 188: 2175–2180.
[18]
Radhakrishnan S, Nguyen LT, Ciric B, Van Keulen VP, Pease LR (2007) B7-DC/PD-L2 cross-linking induces NF-kappaB-dependent protection of dendritic cells from cell death. J Immunol 178: 1426–1432.
[19]
Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, et al. (2009) Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci U S A 106: 14978–14983.
[20]
Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25: 280–288.
[21]
Ghosh P, Sica A, Young HA, Ye J, Franco JL, et al. (1994) Alterations in NF kappa B/Rel family proteins in splenic T-cells from tumor-bearing mice and reversal following therapy. Cancer Res 54: 2969–2972.
[22]
Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, et al. (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66: 11432–11440.
[23]
Ziegler-Heitbrock HW, Petersmann I, Frankenberger M (1997) p50 (NF-kappa B1) is upregulated in LPS tolerant P388D1 murine macrophages. Immunobiology 198: 73–80.
[24]
Winzler C, Rovere P, Rescigno M, Granucci F, Penna G, et al. (1997) Maturation stages of mouse dendritic cells in growth factor-dependent long-term cultures. J Exp Med 185: 317–328.
[25]
Sica A, Saccani A, Borsatti A, Power CA, Wells TN, et al. (1997) Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. J Exp Med 185: 969–974.
[26]
Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DH, et al. (1997) Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol 158: 5676–5684.
[27]
Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, et al. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3: 1097–1101.
[28]
Riboldi E, Frascaroli G, Transidico P, Luini W, Bernasconi S, et al. (2003) Benzydamine inhibits monocyte migration and MAPK activation induced by chemotactic agonists. Br J Pharmacol 140: 377–383.
[29]
Diebold SS, Cotten M, Koch N, Zenke M (2001) MHC class II presentation of endogenously expressed antigens by transfected dendritic cells. Gene Ther 8: 487–493.
[30]
Santambrogio L, Sato AK, Carven GJ, Belyanskaya SL, Strominger JL, et al. (1999) Extracellular antigen processing and presentation by immature dendritic cells. Proc Natl Acad Sci U S A 96: 15056–15061.
[31]
Daro E, Pulendran B, Brasel K, Teepe M, Pettit D, et al. (2000) Polyethylene glycol-modified GM-CSF expands CD11b(high)CD11c(high) but notCD11b(low)CD11c(high) murine dendritic cells in vivo: a comparative analysis with Flt3 ligand. J Immunol 165: 49–58.
[32]
Blander JM, Medzhitov R (2006) On regulation of phagosome maturation and antigen presentation. Nat Immunol 7: 1029–1035.
[33]
Ingulli E, Mondino A, Khoruts A, Jenkins MK (1997) In vivo detection of dendritic cell antigen presentation to CD4(+) T cells. J Exp Med 185: 2133–2141.
[34]
Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, et al. (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84: 1415–1420.
[35]
Chen M, Huang L, Shabier Z, Wang J (2007) Regulation of the lifespan in dendritic cell subsets. Mol Immunol 44: 2558–2565.
[36]
Gao K, Dai DL, Martinka M, Li G (2006) Prognostic significance of nuclear factor-kappaB p105/p50 in human melanoma and its role in cell migration. Cancer Res 66: 8382–8388.
[37]
Liu YJ, Kanzler H, Soumelis V, Gilliet M (2001) Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2: 585–589.
[38]
Dinarello CA (1999) IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 103: 11–24.
[39]
Trinchieri G, Pflanz S, Kastelein RA (2003) The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19: 641–644.
[40]
Laderach D, Compagno D, Danos O, Vainchenker W, Galy A (2003) RNA interference shows critical requirement for NF-kappa B p50 in the production of IL-12 by human dendritic cells. J Immunol 171: 1750–1757.
[41]
Kono S, Kuzuya H, Yamada K, Yoshimasa Y, Okamoto M, et al. (1994) A novel substrate for insulin-sensitive serine/threonine kinase in intact cells. Endocrinology 135: 1529–1536.
[42]
Dissanayake D, Hall H, Berg-Brown N, Elford AR, Hamilton SR, et al. (2011) Nuclear factor-kappaB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T cells. Nat Med 17: 1663–1667.
[43]
Chen Z, O’Shea JJ (2008) Th17 cells: a new fate for differentiating helper T cells. Immunol Res 41: 87–102.
[44]
de Weerd NA, Samarajiwa SA, Hertzog PJ (2007) Type I interferon receptors: biochemistry and biological functions. J Biol Chem 282: 20053–20057.
[45]
Le Bon A, Tough DF (2002) Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14: 432–436.
[46]
Huang L, Baban B, Johnson BA, 3rd, Mellor AL (2010) Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int Rev Immunol 29: 133–155.
[47]
Bellone M, Cantarella D, Castiglioni P, Crosti MC, Ronchetti A, et al. (2000) Relevance of the tumor antigen in the validation of three vaccination strategies for melanoma. J Immunol 165: 2651–2656.
[48]
Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, et al. (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194: 769–779.
[49]
Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30: 636–645.
[50]
Das J, Chen CH, Yang L, Cohn L, Ray P, et al. (2001) A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nat Immunol 2: 45–50.
[51]
Artis D, Kane CM, Fiore J, Zaph C, Shapira S, et al. (2005) Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation. J Immunol 174: 7154–7159.
[52]
Lawrence T, Willoughby DA, Gilroy DW (2002) Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2: 787–795.
[53]
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8: 59–73.
[54]
Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, et al. (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15: 1170–1178.
[55]
Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453: 1122–1126.
[56]
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, et al. (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464: 1357–1361.
[57]
Dinarello CA (1998) Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol 16: 457–499.
[58]
Park D, Lapteva N, Seethammagari M, Slawin KM, Spencer DM (2006) An essential role for Akt1 in dendritic cell function and tumor immunotherapy. Nat Biotechnol 24: 1581–1590.
[59]
Kim JH, Chen J, Majumder N, Lin H, Falo LD Jr, et al. (2005) ‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity. Gene Ther 12: 1517–1525.
[60]
Fallarino F, Vacca C, Orabona C, Belladonna ML, Bianchi R, et al. (2002) Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells. Int Immunol 14: 65–68.
