Critical roles of interferon regulatory factor 4 in CD11b<sup>high</sup>CD8α<sup>–</sup>dendritic cell development

Suzuki, Shingo; Honma, Kiyonobu; Matsuyama, Tomohiro; Suzuki, Kazuo; Toriyama, Kan; Ichinose, Akitada; Yamamoto, Kazuo; Suematsu, Takashi; Nakamura, Michio; Yui, Katsuyuki; Kumatori, Atsushi

doi:10.1073/pnas.0402139101

Cited by 279 publications

(216 citation statements)

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“…Mice lacking a functional IRF4 gene have almost no splenic CD4 1 CD8 2 cDCs. 33,34 In contrast, IRF8 is crucial in the development of mouse CD8 1 cDCs and pDCs. 34,35 IRF8 and IRF4 expression in human DC subsets and monocytes sorted from day 21 Flt3L cultures were analysed by quantitative realtime PCR (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

“…These markers have been used to segregate DC subsets in the spleen, 30,42 the thymus 30,42 and in Flt3L cultures in vitro. 7 Murine DC subsets also have unique developmental origins and specialized functions reflected in the differential expression of and requirement for transcription factors, [33][34][35] expression of TLRs 7,36,37 and production of cytokines. In particular, CD8 1 DCs compared to the CD8 2 DCs require IRF8 and Batf3 for development, express TLR3, produce high levels of IL-12p70 and are efficient at cross-presentation of antigen to CD8 1 T cells both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

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The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

et al. 2012

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Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CD1b/c 1 and CD141 1 CLEC9A 1 conventional DC (cDC) and a plasmacytoid DC (pDC) that is CD304 1 CD123 1 . Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitro from human CD34 1 precursors in the presence of fms-like tyrosine kinase 3 ligand (Flt3L) and thrombopoietin (TPO). The DC subsets so generated, including the CD1b/c 1 and CLEC9A 1 cDCs and CD123 1 pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

et al. 2012

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“…Other genes, i.e. Krüppel family of zinc finger transcription factor Ikaros C, transcription factor PU.1, IRF-2 and IRF-4 (IFN regulatory factor-2 and -4), Notch-dependent transcription factor RBP-J, and TRAF6 (TNF receptor associated factor-6), have also been described to play a role in differentiation of CD4+ DC subset [36][37][38][39][40][41]. The Ig superfamily member, CD40 and Toll-like receptors are receptors known to signal through TRAF6, yet none of those TNFR are implicated in the regulation of DC homeostasis.…”

Section: Noncanonical Nfκb Signaling Cascade Regulates DC Homeostasismentioning

confidence: 99%

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Trez

Ware

2008

Cytokine & Growth Factor Reviews

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Dendritic cells (DC) constitute the most potent antigen presenting cells of the immune system, playing a key role bridging innate and adaptive immune responses. Specialized DC subsets differ depending on their origin, tissue location and the influence of trophic factors, the latter remain to be fully understood. Stromal cell and myeloid-associated Lymphotoxin-β receptor (LTβR) signaling is required for the local proliferation of lymphoid tissue DC. This review focuses the LTβR signaling cascade as a crucial positive trophic signal in the homeostasis of DC subsets. The noncanonical coreceptor pathway comprised of the Immunoglobulin (Ig) superfamily member, B and T lymphocyte attenuator (BTLA) and TNFR superfamily member, Herpesvirus entry mediator (HVEM) counter regulates the trophic signaling by LTβR. Together both pathways form an integrated signaling circuit achieving homeostasis of DC subsets.Keywords dendritic cells; homeostasis; TNF superfamily; cosignaling; lymphotoxin; herpesvirus entry mediator Dendritic CellsDendritic cells (DC) originate from hematopoietic precursors and can be divided in several subsets depending on their anatomical location, surface phenotype and function. For example, two broad classes of DC are the peripheral migratory DC and the lymphoid tissue-resident DC [1]. The migratory DC, i.e. the dermal DC and Langerhans cells, can be considered as sentinels of the immune system as they form a sensing barrier in peripheral tissues at the interface with environment. The lymphoid tissue-resident DC include the splenic and thymic DC.Dendritic cells are specialized in the capture, transport, processing and presentation of antigens. In the presence of a microbial stimulus, these steps are associated with further DC differentiation (maturation) characterized by upregulation of costimulatory and major histocompatibility complex (MHC) molecules. As DC become activated they migrate to or Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Both spleen and lymph node lymphoid tissue-resident DC possess a half-life of about three days. Despite their rapid turnover, little is known about the factors controlling immediate precursors and homeostasis in vivo. In earlier studies, CD8α expression was used to distinguish between "lymphoid" and "myeloid" DC. However, more recent experiments showed that different DC subsets could differentiate from both lymphoid and myeloid precursors [6,7]. CD8α marker remains very useful to discriminate between subsets, but no longer defines a subset origin. Recently, the group of Shortman provided in vivo and in vitro evidence fo...

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“…Studies with gene targeted mice have revealed several transcription factors implicated in pDC development, including STAT3, which is involved in FMS-like tryrosine kinase 3 ligand (Flt3L)-dependent DC differentiation [12], Ikaros [13], interferon regulatory factor (IRF)-4 and IRF-8 [14][15][16], Gfi1 [17], and XBP1 [18]. Interestingly, deficiency in some of these factors results in specific ablation of just the pDC subset, whereas others additionally affect the development of other lymphoid-tissue resident or skin DC.…”

Section: Introductionmentioning

confidence: 99%

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

et al. 2008

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Plasmacytoid dendritic cells (pDC) are central players in the innate and adaptive immune response against viral infections. The molecular mechanism that underlies pDC development from progenitor cells is only beginning to be elucidated. Previously, we reported that the Ets factor Spi-B and the inhibitors of DNA binding protein 2 (Id2) or Id3, which antagonize E-protein activity, are crucially involved in promoting or impairing pDC development, respectively. Here we show that the basic helix-loop-helix protein E2-2 is predominantly expressed in pDC, but not in their progenitor cells or conventional DC. Forced expression of E2-2 in progenitor cells stimulated pDC development. Conversely, inhibition of E2-2 expression by RNA interference impaired the generation of pDC suggesting a key role of E2-2 in development of these cells. Notably, Spi-B was unable to overcome the Id2 enforced block in pDC development and moreover Spi-B transduced pDC expressed reduced Id2 levels. This might indicate that Spi-B contributes to pDC development by promoting E2-2 activity. Consistent with notion, simultaneous overexpression of E2-2 and Spi-B in progenitor cells further stimulated pDC development. Together our results provide additional insight into the transcriptional network controlling pDC development as evidenced by the joint venture of E2-2 and Spi-B.Key words: E2-2/TCF4 Á E-proteins Á Human development Á Plasmacytoid dendritic cell Á Spi-B Supporting Information available online See accompanying commentary by Esashi and Liu IntroductionThe ability of dendritic cells (DC) to capture and present antigenic peptides has established a function in both the adaptive and innate branches of the immune system. Extensive characterization of DC has revealed the existence of many different DC subsets with distinct cell surface phenotype, cytokine expression profile, and anatomical localization [1]. One member of the DC family is the plasmacytoid DC (pDC), which is hallmarked by their capacity to produce high levels of type I interferons and hence are also known as natural type I interferons producing cells [2]. Eur. J. Immunol. 2008. 38: 2389-2400 DOI 10.1002 HIGHLIGHTS 2389Frontline pDC are detected in blood and most tissues, including spleen, lymph nodes, and thymus [2,3]. Previously, we described that at least two developmental pathways exist for pDC, an extrathymic and an intrathymic pathway [4]. The requirements for the development of DC subsets are not fully understood. In mice it has been shown that conventional DC (cDC) and pDC can develop from minor Flt3 1 subpopulations within the common myeloid and the common lymphoid progenitor pools [5][6][7]. Recently, this pool was narrowed down to a DC committed precursor (pro-DC) that can only develop into cells of the DC lineages [8,9]. It is not clear yet at what point in DC development the commitment to a subpopulation is accomplished. Also, human pDC can be derived from both myeloid and lymphoid progenitor cells [10,11]. A better understanding of the molecular mechanisms that control...

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Critical roles of interferon regulatory factor 4 in CD11b^highCD8α^–dendritic cell development

Cited by 279 publications

References 55 publications

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

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Critical roles of interferon regulatory factor 4 in CD11bhighCD8α–dendritic cell development

Cited by 279 publications

References 55 publications

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

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Critical roles of interferon regulatory factor 4 in CD11b^highCD8α^–dendritic cell development