Impact of HDAC inhibitors on dendritic cell functions
2012; Elsevier BV; Volume: 40; Issue: 10 Linguagem: Inglês
10.1016/j.exphem.2012.06.008
ISSN1873-2399
AutoresJihane Frikeche, Zinaida Perić, Éolia Brissot, Marc Grégoire, Béatrice Gaugler, Mohamad Mohty,
Tópico(s)Protein Degradation and Inhibitors
ResumoHistone deacetylase inhibitors are presently used in the routine clinic treatment against cancers. Recent data have established that some of these treatments have potent anti-inflammatory or immunomodulatory effects at noncytotoxic doses that might be of benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of histone deacetylase inhibitors to modulate the immune system. Dendritic cells are professional antigen presenting cells that play a major role in this immune system. Data summarized in this review brings some novel information on the impact of histone deacetylase inhibitors on dendritic cell functions, which may have broader implications for immunotherapeutic strategies. Histone deacetylase inhibitors are presently used in the routine clinic treatment against cancers. Recent data have established that some of these treatments have potent anti-inflammatory or immunomodulatory effects at noncytotoxic doses that might be of benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of histone deacetylase inhibitors to modulate the immune system. Dendritic cells are professional antigen presenting cells that play a major role in this immune system. Data summarized in this review brings some novel information on the impact of histone deacetylase inhibitors on dendritic cell functions, which may have broader implications for immunotherapeutic strategies. Dendritic cells (DCs) are the most potent antigen-presenting cells (APC) in vitro and in vivo. They play a key role in the initiation of immune responses and are considered to be promising targets for immunotherapy [1Palucka A.K. Ueno H. Fay J. Banchereau J. Dendritic cells: a critical player in cancer therapy?.J Immunother. 2008; 31: 793-805Crossref PubMed Scopus (63) Google Scholar]. DCs induce effective immunity against pathogens and "altered self" like tumor, while maintaining tolerance to self-antigens (Ags) [2Banchereau J. Steinman R.M. Dendritic cells and the control of immunity.Nature. 1998; 392: 245-252Crossref PubMed Scopus (12025) Google Scholar]. In mice, constitutive ablation of DCs breaks self-tolerance, producing spontaneous autoimmunity [3Ohnmacht C. Pullner A. King S.B. et al.Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity.J Exp Med. 2009; 206: 549-559Crossref PubMed Scopus (429) Google Scholar]. Based on many studies observed in mouse models, DCs have been classified into two major classes: conventional DCs and plasmacytoid DCs [4Shortman K. Liu Y.J. Mouse and human dendritic cell subtypes.Nat Rev Immunol. 2002; 2: 151-161Crossref PubMed Scopus (1865) Google Scholar, 5Villadangos J.A. Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo.Nat Rev Immunol. 2007; 7: 543-555Crossref PubMed Scopus (472) Google Scholar]. Although conventional DCs are the most studied cells, the functions of plasmacytoid DCs are more specific. Plasmacytoid DCs are a rare population of circulating cells that have the unique ability to rapidly produce large quantities of type I interferon in response to viral infections [6Colonna M. Trinchieri G. Liu Y.J. Plasmacytoid dendritic cells in immunity.Nat Immunol. 2004; 5: 1219-1226Crossref PubMed Scopus (1322) Google Scholar]. Under steady-state conditions they are present in the bloodstream and secondary lymphoid organs, but are normally absent from most peripheral tissues [7Wollenberg A. Mommaas M. Oppel T. Schottdorf E.M. Gunther S. Moderer M. Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases.J Invest Dermatol. 2002; 118: 327-334Crossref PubMed Scopus (166) Google Scholar, 8Gilliet M. Conrad C. Geiges M. et al.Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.Arch Dermatol. 2004; 140: 1490-1495Crossref PubMed Scopus (327) Google Scholar]. From the peripheral blood, plasmacytoid DCs are recruited to inflammation sites, where they accumulate and play a significant immunomodulatory role in many animal viral models and disease settings [9Langlois R.A. Legge K.L. Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T cells.J Immunol. 2010; 184: 4440-4446Crossref PubMed Scopus (42) Google Scholar, 10Diana J. Griseri T. Lagaye S. et al.NKT cell-plasmacytoid dendritic cell cooperation via OX40 controls viral infection in a tissue-specific manner.Immunity. 2009; 30: 289-299Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. Conventional DCs, on other hand, are localized in all peripheral tissues in proximity to the epithelium of body surfaces, where there is risk of invasion by pathogens. These DCs can capture pathogen-derived material from the periphery via blood or afferent lymphatics to draining lymph nodes, where they activate T cells. In the thymus, DCs have an important role in maintaining self-tolerance by negatively selecting autoreactive T cells and positively selecting regulatory T cells (Tregs) [11Liu Y.J. A unified theory of central tolerance in the thymus.Trends Immunol. 2006; 27: 215-221Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. These DCs are also localized in secondary lymphoid tissues (spleen and lymph nodes). Some lymphoid-resident DCs subsets have been described in mice, including CD8α+ DCs responsible for cross-presentation of exogenous Ags on major histocompatibility complex class I, and CD8α− DCs specialized in CD4+ T-cell activation [12Shortman K. Heath W.R. The CD8+ dendritic cell subset.Immunol Rev. 2010; 234: 18-31Crossref PubMed Scopus (378) Google Scholar]. Another DCs subpopulation that has been described relates to inflammatory DCs, which seem to derive from monocytes during inflammation. This differentiation of monocytes into DCs does not happen under noninflammatory, steady-state conditions [13Merad M. Ginhoux F. Dendritic cell genealogy: a new stem or just another branch?.Nat Immunol. 2007; 8: 1199-1201Crossref PubMed Scopus (13) Google Scholar, 14Shortman K. Naik S.H. Steady-state and inflammatory dendritic-cell development.Nat Rev Immunol. 2007; 7: 19-30Crossref PubMed Scopus (939) Google Scholar]. Human monocyte-derived DCs generated in vitro in response to granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4 are similar to these inflammatory DCs [14Shortman K. Naik S.H. Steady-state and inflammatory dendritic-cell development.Nat Rev Immunol. 2007; 7: 19-30Crossref PubMed Scopus (939) Google Scholar]. Under steady-state conditions, in peripheral tissues, DCs are in an immature state, constantly capturing Ags but lacking the ability to efficiently process and present these Ags to T cells. In contrast, when there are signals associated with infection and tissue damage, DCs mature into powerful APCs and migrate to secondary lymphoid organs. There they activate naïve and memory T cells and enhance effector T-cell responses. Mature DCs supply naïve T cells with major histocompatibility complex/peptide complexes (signal 1) and costimulatory molecules (signal 2) that synergistically promote development of Ag-specific T cells. Moreover, DCs provide signal 3: soluble or membrane molecules that are responsible for polarization of distinct T-cell subset (i.e., Th1, Th2, Th17, Treg...). The various T-cell subsets control different components of cellular and humoral immunity [15Kalinski P. Hilkens C.M. Wierenga E.A. Kapsenberg M.L. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal.Immunol Today. 1999; 20: 561-567Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar]. A typical example of signal 3 is IL-12. It is secreted by DCs in response to some microbes and effectively leads to development of Th1 cells [16Macatonia S.E. Hosken N.A. Litton M. et al.Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells.J Immunol. 1995; 154: 5071-5079PubMed Google Scholar, 17Hilkens C.M. Kalinski P. de Boer M. Kapsenberg M.L. Human dendritic cells require exogenous interleukin-12-inducing factors to direct the development of naive T-helper cells toward the Th1 phenotype.Blood. 1997; 90: 1920-1926Crossref PubMed Google Scholar]. Pathogen- and tissue-derived molecules can change the nature of signal 3. Thus, DCs operate as a connection between innate and adaptive immunity by transmitting essential information on the nature of damage and infection in the periphery to naïve T cells in the lymph nodes. Studies performed in the last few years have confirmed the hypothesis that immature DCs can induce tolerance, while mature DCs can induce immunity [18Cools N. Ponsaerts P. Van Tendeloo V.F. Berneman Z.N. Balancing between immunity and tolerance: an interplay between dendritic cells, regulatory T cells, and effector T cells.J Leukoc Biol. 2007; 82: 1365-1374Crossref PubMed Scopus (174) Google Scholar]. For example, in 2003, Probst et al. [19Probst H.C. Lagnel J. Kollias G. van den Broek M. Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance.Immunity. 2003; 18: 713-720Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar] generated a Cre/LoxP-based system that permitted inducible Ag presentation by DCs in vivo under steady-state or immune-activating conditions. In this study, Ags presented by resting immature DCs induced Ag-specific tolerance; whereas Ags presented by mature DCs promoted cytotoxic T lymphocytes expansion and protective effector functions. In contrast, it has become increasingly clear that the maturation state of DCs is not always linked with their activating or protective immune functions. For instance, mature DCs can efficiently expand naturally occurring Tregs [20Tarbell K.V. Yamazaki S. Olson K. Toy P. Steinman R.M. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes.J Exp Med. 2004; 199: 1467-1477Crossref PubMed Scopus (578) Google Scholar, 21Watanabe N. Wang Y.H. Lee H.K. Ito T. Cao W. Liu Y.J. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus.Nature. 2005; 436: 1181-1185Crossref PubMed Scopus (595) Google Scholar, 22Yamazaki S. Patel M. Harper A. et al.Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction.Proc Natl Acad Sci U S A. 2006; 103: 2758-2763Crossref PubMed Scopus (171) Google Scholar]. Also, some microbial products cause the maturation of DCs by increasing major histocompatibility complex II and costimulatory molecule expression, but these DCs secrete anti-inflammatory IL-10 and provoke the expansion of IL-10–producing Tregs [23McGuirk P. McCann C. Mills K.H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis.J Exp Med. 2002; 195: 221-231Crossref PubMed Scopus (551) Google Scholar, 24van der Kleij D. Latz E. Brouwers J.F. et al.A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization.J Biol Chem. 2002; 277: 48122-48129Crossref PubMed Scopus (489) Google Scholar]. It is now known that mature DCs can demonstrate tolerogenic functions, and that their tolerogenicity can be promoted by signals that they receive during maturation. For example, immunosuppressive cytokines (IL-10, transforming growth factor–β) [25Steinbrink K. Jonuleit H. Muller G. Schuler G. Knop J. Enk A.H. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells.Blood. 1999; 93: 1634-1642PubMed Google Scholar, 26Sato K. Yamashita N. Baba M. Matsuyama T. Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse.Immunity. 2003; 18: 367-379Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 27Lan Y.Y. Wang Z. Raimondi G. et al."Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig.J Immunol. 2006; 177: 5868-5877PubMed Google Scholar] or some pathogen-derived molecules [24van der Kleij D. Latz E. Brouwers J.F. et al.A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization.J Biol Chem. 2002; 277: 48122-48129Crossref PubMed Scopus (489) Google Scholar] have all been shown to drive the differentiation of tolerogenic DCs. Acetylation of histones represents one of several post-translational modifications. This epigenetic regulation of gene expression is controlled by the opposing activities of two enzymes, histone deacetylases (HDACs) and histone acetyltransferases. Histone acetylation by histone acetyltransferases is associated with activation of transcription through relaxed chromatin structure, whereas deacetylation by HDACs induces a more condensed or inactive chromatin state, leading to gene repression. Emerging data demonstrate that HDACs also modify the activity of diverse types of nonhistone cellular proteins [28Minucci S. Pelicci P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.Nat Rev Cancer. 2006; 6: 38-51Crossref PubMed Scopus (1909) Google Scholar]. It is therefore possible that acetylation state of nonhistone proteins induced by histone acetyltransferases and HDACs is an important in regulate function, stability, and interactions between proteins and proteins and DNA [29Kim S.C. Sprung R. Chen Y. et al.Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.Mol Cell. 2006; 23: 607-618Abstract Full Text Full Text PDF PubMed Scopus (1179) Google Scholar]. The imbalance of acetylation and deacetylation may be responsible for a wide range of human disorders, including oncogenesis and immune dysfunction [30Redner R.L. Wang J. Liu J.M. Chromatin remodeling and leukemia: new therapeutic paradigms.Blood. 1999; 94: 417-428Crossref PubMed Google Scholar]. HDACs include a family of 18 genes subdivided into the following distinct classes: class I (HDAC 1, 2, 3, and 8), class II (HDAC 5, 6, 7, 9, and 10), and class IV (HDAC 11) have sequence similarity and require Zn+ for enzymatic activity [31Bolden J.E. Peart M.J. Johnstone R.W. Anticancer activities of histone deacetylase inhibitors.Nat Rev Drug Discov. 2006; 5: 769-784Crossref PubMed Scopus (2453) Google Scholar, 32Yang X.J. Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.Nat Rev Mol Cell Biol. 2008; 9: 206-218Crossref PubMed Scopus (932) Google Scholar, 33Yang X.J. Seto E. Lysine acetylation: codified crosstalk with other posttranslational modifications.Mol Cell. 2008; 31: 449-461Abstract Full Text Full Text PDF PubMed Scopus (749) Google Scholar, 34Walkinshaw D.R. Yang X.J. Histone deacetylase inhibitors as novel anticancer therapeutics.Curr Oncol. 2008; 15: 237-243PubMed Google Scholar, 35Mai A. Altucci L. Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead.Int J Biochem Cell Biol. 2009; 41: 199-213Crossref PubMed Scopus (169) Google Scholar]. Class III is a structurally distinct NAD+-dependent subfamily and belong to the Sirtuin family [32Yang X.J. Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.Nat Rev Mol Cell Biol. 2008; 9: 206-218Crossref PubMed Scopus (932) Google Scholar]. The classical HDAC inhibitors (HDACIs), which act on the zinc-dependent HDACs (HDAC 1–11), include benzamides (MS275), short-chain fatty acids (sodium butyrate and valproic acid [VPA]), hydroxamic acids (trichostatin A [TSA] and suberoylanilide hydroxamic acid [SAHA]) and cyclic tetrapeptides like trapoxin and depsipeptide [31Bolden J.E. Peart M.J. Johnstone R.W. Anticancer activities of histone deacetylase inhibitors.Nat Rev Drug Discov. 2006; 5: 769-784Crossref PubMed Scopus (2453) Google Scholar, 34Walkinshaw D.R. Yang X.J. Histone deacetylase inhibitors as novel anticancer therapeutics.Curr Oncol. 2008; 15: 237-243PubMed Google Scholar, 35Mai A. Altucci L. Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead.Int J Biochem Cell Biol. 2009; 41: 199-213Crossref PubMed Scopus (169) Google Scholar] (Table 1). Two of them, SAHA and ITF 2357, were approved by the US Food and Drug Administration for treatment of cutaneous T-cell lymphoma [36Mann B.S. Johnson J.R. Cohen M.H. Justice R. Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.Oncologist. 2007; 12: 1247-1252Crossref PubMed Scopus (972) Google Scholar, 37Duvic M. Talpur R. Ni X. et al.Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL).Blood. 2007; 109: 31-39Crossref PubMed Scopus (923) Google Scholar]. Other HDACIs, such as butyrate and VPA, have long been utilized clinically in nononcologic contexts. For example, butyrate continues to be used as a therapy for inflammatory bowel disease, although whether its benefits are due to inhibition of HDAC activity stays controversial [38Gibson P.R. The intracellular target of butyrate's actions: HDAC or HDON'T?.Gut. 2000; 46: 447-448Crossref PubMed Scopus (31) Google Scholar]. Similarly, for a while, VPA has been used as an anticonvulsive activity. There are no data available to confirm whether prolonged treatment of epileptic patients with VPA also protects against comorbid immunoinflammatory diseases through inhibition of HDACs [39Vezzani A. Granata T. Brain inflammation in epilepsy: experimental and clinical evidence.Epilepsia. 2005; 46: 1724-1743Crossref PubMed Scopus (789) Google Scholar].Table 1Different classes of HDAC inhibitorsHDACIsHDAC specificityClinical trialTumorsHydroxamic acidstrichostatin AClass I, IILeukemia, lymphoma, myeloma, various solid tumorsSAHAClass I, IIFDA approvalCutaneous T-cell lymphomaShort-chain fatty acidsButyrateClass I, lIaPhase I, IILeukemia, lymphoma, intestinal cancersVPAClass I, llaPhase I, II, IIILeukemia, various solid tumors, myelodysplasiaBenzamidesMS-275Class IPhase I, IISolid tumors, leukemia, lymphomaFDA = US Food and Drug Administration. Open table in a new tab FDA = US Food and Drug Administration. At high concentrations, HDACIs exhibit antitumor properties and are considered cytotoxic. Approximately 80 clinical trials with HDACIs are currently ongoing and testing more than a dozen drugs in various solid and hematologic malignancies [40Tan J. Cang S. Ma Y. Petrillo R.L. Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents.J Hematol Oncol. 2010; 3: 5Crossref PubMed Scopus (366) Google Scholar]. The anticancer potential of HDACIs arises from their capacity to influence several cellular processes that are usually deregulated in tumor cells. In general, inhibition of the cell cycle, activation of differentiation, and induction of apoptosis are the important antitumor activities of HDACIs (Fig. 1). HDACIs alter the differentiation of leukemia circulating cells [41Puccetti E. Zheng X. Brambilla D. et al.The integrity of the charged pocket in the BTB/POZ domain is essential for the phenotype induced by the leukemia-associated t(11;17) fusion protein PLZF/RARalpha.Cancer Res. 2005; 65: 6080-6088Crossref PubMed Scopus (19) Google Scholar], of breast cancer cell lines [42Bali P. Pranpat M. 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Anticancer activities of histone deacetylase inhibitors.Nat Rev Drug Discov. 2006; 5: 769-784Crossref PubMed Scopus (2453) Google Scholar]. Recent preclinical studies demonstrated a direct link between initiation of tumor cell apoptosis and therapeutic efficacy [45Nebbioso A. Clarke N. Voltz E. et al.Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells.Nat Med. 2005; 11: 77-84Crossref PubMed Scopus (455) Google Scholar, 46Insinga A. Monestiroli S. Ronzoni S. et al.Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway.Nat Med. 2005; 11: 71-76Crossref PubMed Scopus (480) Google Scholar, 47Lindemann R.K. Newbold A. Whitecross K.F. et al.Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma.Proc Natl Acad Sci U S A. 2007; 104: 8071-8076Crossref PubMed Scopus (176) Google Scholar, 48Newbold A. Lindemann R.K. 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Xu W.S. et al.Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors.Proc Natl Acad Sci U S A. 2005; 102: 673-678Crossref PubMed Scopus (437) Google Scholar]. HDACIs can also cause an increase in the level of thioredoxin, a major reducing protein for many targets in normal cells but not in transformed cells. In the case of tumor cells, they induce the binding of thioredoxin to thioredoxin binding protein (TBP2), its inactivation, and the induction of cell death [51Dokmanovic M. Marks P.A. Prospects: histone deacetylase inhibitors.J Cell Biochem. 2005; 96: 293-304Crossref PubMed Scopus (421) Google Scholar]. This selective induction of tumor cell death can also be explained by the selective increase of tumor necrosis factor–related apoptosis-inducing ligand and its receptor (DR5) expression induced by HDACIs [52Srivastava R.K. Kurzrock R. Shankar S. MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo.Mol Cancer Ther. 2010; 9: 3254-3266Crossref PubMed Scopus (104) Google Scholar]. In addition, combining HDACIs with other proapoptotic agents can result in synergistic apoptosis and higher antitumor activities [31Bolden J.E. Peart M.J. Johnstone R.W. Anticancer activities of histone deacetylase inhibitors.Nat Rev Drug Discov. 2006; 5: 769-784Crossref PubMed Scopus (2453) Google Scholar, 53Frew A.J. Lindemann R.K. Martin B.P. et al.Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.Proc Natl Acad Sci U S A. 2008; 105: 11317-11322Crossref PubMed Scopus (112) Google Scholar]. 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Histone deacetylase inhibitors: new hope for rheumatoid arthritis?.Curr Pharm Des. 2008; 14: 803-820Crossref PubMed Scopus (55) Google Scholar]. HDACIs have direct and indirect impacts on a variety of immune cell subsets. By reducing the secretion of inflammatory cytokines, they play an important role in the negative regulation of APCs. HDACIs also increase the number and function of naturally occurring Tregs, exert various effects on natural killer (NK) cell function, and inhibit the activity of genes involved in immune functions of macrophages [60Roger T. Lugrin J. Le Roy D. et al.Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection.Blood. 2011; 117: 1205-1217Crossref PubMed Scopus (242) Google Scholar]. Because of their central role in orchestrating innate and adaptive immunity, many groups have investigated the effect of HDACIs on DCs. Most results suggest that HDACIs affect biologic activities of DCs at different levels. CD40 is a well-characterized costimulatory molecule, with its ligand CD40L present on the surface of T cells. It is upregulated on activated DCs and functions as a trigger for the expression of two other important costimulatory molecules, CD80 and CD86 [61Caux C. Massacrier C. Vanbervliet B. et al.Activation of human dendritic cells through CD40 cross-linking.J Exp Med. 1994; 180: 1263-1272Crossref PubMed Scopus (1168) Google Scholar]. CD40–CD40L interaction is also essential for IL-12 secretion, which polarizes T-cell responses to a T-helper 1 (Th1 type) [62Cella M. Sallusto F. Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells.Curr Opin Immunol. 1997; 9: 10-16Crossref PubMed Scopus (1148) Google Scholar]. CD80 and CD86 are expressed on DCs and bind to CD28 on T cells. Costimulation of CD28 with CD80 and CD86 induces T-lymphocyte proliferation and cytokine secretion. CD83 is a maturation marker on DCs [63Zhou L.J. Tedder T.F. CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells.Proc Natl Acad Sci U S A. 1996; 93: 2588-2592Crossref PubMed Scopus (953) Google Scholar]. Weakly expressed on immature DCs, it is strongly upregulated during DCs maturation together with CD80 and CD86. Previous studies in mice have shown that this molecule positively regulates CD4+ T development as well as major histocompatibility complex class II Ag expression [64Kuwano Y. Prazma C.M. Yazawa N. et al.CD83 influences cell-surface MHC class II expression on B cells and other antigen-presenting cells.Int Immunol. 2007; 19: 977-992Crossref PubMed Scopus (40) Google Scholar]. The effect of several HDACIs on these costimulation molecules was investigated in numerous studies. In 2007, for example Nencioni et al. showed that two HDACIs, MS-275 and VPA, affect the expression of costimulation and adhesion molecules on human monocyte-derived DCs [65Nencioni A. Beck J. Werth D. et al.Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity.Clin Cancer Res. 2007; 13: 3933-3941Crossref PubMed Scopus (131) Google Scholar]. They observed an important reduction of CD40, CD80, and CD83 expression, whereas the expression of CD86 was minimally affected. Similar observations were made by our group using VPA [66Frikeche J. Simon T. Brissot E. Gregoire M. Gaugler B. Mohty M. Impact of valproic acid on dendritic cells function.Immunobiology. 2012; 217: 704-710Crossref PubMed Scopus (31) Google Scholar]. Exposure to LBH589, another HDACIs, also affected the costimulatory molecule expre
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