Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation

Lugt, Bryan Vander; Riddell, Jeremy; Khan, Aly A.; Hackney, Jason A.; Lesch, Justin; DeVoss, Jason; Weirauch, Matthew T.; Singh, Harinder; Mellman, Ira

doi:10.1083/jcb.201512012

Cited by 79 publications

(75 citation statements)

References 48 publications

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“…Interestingly, Aldh1a2 was one of the highly expressed genes in PD-L2 + BMDCs (23). A recent study regarding conditional deletion of the Irf4 gene in CD11c + DCs showed that the development of tolerogenic DCs possessing the expression and the enzymatic activity of RALDH2 is diminished (24). In the current study, to distinguish the development process and the gene regulation of DCs, we used the knockdown experiments using siRNA against GM-CSF-derived BMDCs and Flt3L-BMDCs at the later stage of development and elucidated the mechanism of cell typespecific transcription of Aldh1a2.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we found that the expression of IRF4 and the binding of PU.1 to the Aldh1a2 promoter were enhanced in GM-CSF-stimulated cells, in which the Aldh1a2 transcription was markedly increased. Considering that the IRF4 level in RALDH2-positive DCs is higher than those in other DCs in vivo (18,23,24), the binding degree of PU.1 and IRF4 may be associated with the potential for transcription of the Aldh1a2 gene.…”

Section: Discussionmentioning

confidence: 99%

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The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell–Specific Expression of RALDH2

Yashiro

Yamaguchi

Watanuki

et al. 2018

The Journal of Immunology

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RALDH2 expressed in dendritic cells (DCs) plays a critical role in the development of regulatory T cells in mesenteric lymph nodes. Despite the importance of RALDH2 in intestinal immunity, little is known about the mechanism of DC-specific expression of RALDH2. In the current study, we focused on the hematopoietic cell–specific transcription factors PU.1 and IRF4 as the determinants of Aldh1a2 gene expression. The mRNA level of Aldh1a2, and subsequently the enzyme activity, were decreased by knockdown of PU.1 and IRF4 in bone marrow–derived DCs (BMDCs) of BALB/c mice. Chromatin immunoprecipitation assays showed that PU.1 and IRF4 bound to the Aldh1a2 gene ∼2 kb upstream from the transcription start site in BMDCs. A reporter assay and an EMSA revealed that the Aldh1a2 promoter was synergistically transactivated by a heterodimer composed with PU.1 and IRF4 via the EICE motif at −1961/−1952 of the gene. The effect of small interfering RNAs for Spi1 and Irf4 and specific binding of PU.1 and IRF4 on the Aldh1a2 gene were also observed in DCs freshly isolated from spleen and mesenteric lymph nodes, respectively. GM-CSF stimulation upregulated the Aldh1a2 transcription in Flt3 ligand–generated BMDCs, in which the IRF4 expression and the PU.1 recruitment to the Aldh1a2 promoter were enhanced. We conclude that PU.1 and IRF4 are transactivators of the Aldh1a2 gene in vitro and ex vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell–Specific Expression of RALDH2

Yashiro

Yamaguchi

Watanuki

et al. 2018

The Journal of Immunology

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“…However, in the presence of microbial products, DCs mature and activate nuclear factor kB, which facilitates the generation of effector T cells and an immunogenic profile. 58 Interestingly, the maturation state of DCs can be affected by their interaction with different types of cancer cells. Steady-state immature DCs are maintained and suppressed by cancer cells in a tumor and are also referred to as tumor-infiltrating DCs.…”

Section: Dcsmentioning

confidence: 99%

The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions

Guttman‐Yassky

Zhou

Krueger

2019

Journal of Allergy and Clinical Immunology

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Skin is replete with immunocompetent cells that modulate signaling pathways to maintain a salubrious immunogenic/ tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underused with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, 2 key classes include dendritic cells and regulatory T (Treg) cells. Immature dendritic cells are the first line of defense, patrolling the periphery, sampling antigens, and secreting cytokines that suppress immune cells and promote the survival of Treg cells. Skin-homing Treg cells also play a critical role in mitigating the reactivity of immune cells, secreting high levels of cytokines that promote tolerance. Therapeutic approaches that capitalize on our knowledge of the rich cellular and molecular environment are emerging and show great promise. We will discuss the advantages and challenges of 5 such strategies and how these therapies might mitigate the atopic march by facilitating tolerance. We conclude that skin is a multifaceted structure that provides a fertile ground for therapeutic discovery. Accordingly, ongoing work in this domain will no doubt continue to deliver exciting progress for improved health outcomes. (J Allergy Clin Immunol 2019;144:362-74.)

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“…To explore if IRF4 along with its ETS and AP-1 family partners, PU.1 and BATF3 could be directly controlling the expression of antigen cross-presentation genes in human LCs, we performed genome-wide chromatin profiling and transcription factor motif enrichment analyses. This approach enables the inference of transcriptional regulatory sequences and the transcription factors that are acting to control gene activity in distinct cell types and cell states 39,57 . Notably, tri-methylation at lysine 4 of histone 3 (H3K4Me3) marks active promoters 58 , whereas acetylation of lysine 27 of histone 3 (H3K27Ac) marks active transcriptional enhancers; the latter have been postulated to be the primary determinants of tissue-specific gene expression 59,60 .…”

Section: Enrichment Of Irf Composite Elements In Chromatin Implicatesmentioning

confidence: 99%

“…IRF4 and IRF8 are critical for all aspects of DC biology, controlling a wide range of functions. These include induction of innate responses elicited via pattern recognition receptors TLR, NOD, and RIG during viral and bacterial infection [36][37][38] , cell activation, and efficient antigen uptake, presentation and cross-presentation 23,33,39 , migration and tolerance induction 39,40 . Interestingly, it has been postulated that the ability of murine DC subsets to efficiently activate CD8 and CD4 T cells, depending on the presentation of antigen in the context of MHC class I and II, is determined by the relative expression of IRF8 and IRF4, respectively 33 .…”

Section: Introductionmentioning

confidence: 99%

Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells

Polak

Sirvent

Clayton

et al. 2019

Preprint

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Langerhans cells (LCs) in the epidermis present MHC I and MHC II-restricted antigens thereby priming either CD8 or CD4 T cell immune responses. The genomic programs and transcription factors regulating antigen presentation in LCs remain to be elucidated. We show human LCs are highly efficient in MHC I-antigen cross-presentation but lack the transcription factor IRF8 that is critical in dendritic cells. LC migration from the epidermis enhances their ability to cross-present antigens and is accompanied by the induction of the transcription factor IRF4, whose expression is correlated by scRNA-seq with genes involved in ubiquitin-dependent protein degradation. Chromatin profiling reveals enrichment of EICE and AICE composite DNA binding motifs in regulatory regions of antigen-presentation genes, which can be recognized by IRF4 in conjunction with PU.1 or BATF3 expressed in LCs. Thus, the genomic programming of human LCs including inducible expression of IRF4 with enhanced cross-presentation distinguishes them from conventional dendritic cells.

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Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation

Cited by 79 publications

References 48 publications

The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell–Specific Expression of RALDH2

The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell–Specific Expression of RALDH2

The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions

Genomic programming of antigen cross-presentation in IRF4-expressing human Langerhans cells

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