Epidermal Langerhans Cell-Targeted Gene Expression by a Dectin-2 Promoter

Bonkobara, Makoto; Zukas, Paul K.; Shikano, Sojin; Nakamura, Shinichiro; Cruz, Ponciano D.; Ariizumi, Kiyoshi

doi:10.4049/jimmunol.167.12.6893

Cited by 43 publications

(49 citation statements)

References 50 publications

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“…2,3 Promoter activity is also essential for the development of strong immune responses to transfected antigens. Of the other DCassociated promoters that have been described in the literature (fascin, 20 dc-stamp, 23 cd11c, 33 dectin-2 19 and the promoter for murine MHC class II 34 ), the fascin promoter appears the most promising because of its high activity. Fascin promoter constructs are capable of inducing humoral and cellular responses after in vivo gene-gun vaccination to the same extent as those caused by CMV-driven constructs.…”

Section: Discussionmentioning

confidence: 99%

Targeting dendritic cells with antigen via dendritic cell-associated promoters

et al. 2012

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The induction of tumor-specific immune responses is largely dependent on the ability of dendritic cells (DCs) to present tumor-associated antigens to T lymphocytes. Therefore, we investigated the use of DC-associated promoter-driven genetic vaccines to specifically target DC in vivo. Restricted expression of vaccine-encoding genes in DC should enhance specificity and improves their safety for clinical applications. Hereto, 3 --5 kb upstream sequences of the murine genes encoding CD11c, DC-SIGN, DC-STAMP and Langerin were isolated, characterized and subcloned into enhanced green fluorescent protein (EGFP) reporter constructs. Upon electroporation, EGFP was expressed in DC cell lines, but not in other cell lines, confirming DCrestricted promoter activity. When these promoters were cloned into a construct upstream of the gene for ovalbumin (OVA), it appeared that DC-STAMP promoter-driven expression of OVA (pDCSTAMP/OVA) in DC yielded the most efficient OVA-specific CD4 þ and CD8 þ T-cell responses in vitro. Administration of pDC-STAMP/OVA in vivo, using the tattoo gun vaccination system, evoked specific immune responses as evidenced in a mouse tumor model. Adoptively transferred pDC-STAMP/OVA-transfected DCs induced strong CD8 þ T-cell proliferation in vivo. These experiments demonstrate that our DC-directed promoter constructs are potential tools to restrict antigen expression in DC and could be implemented to modulate DC function by the introduction of relevant proteins.

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Section: Discussionmentioning

confidence: 99%

Targeting dendritic cells with antigen via dendritic cell-associated promoters

et al. 2012

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“…Ariizumi et al reported Dectin-2 as a transcript present in several splice forms, which was highly expressed by a Langerhans-cell-like skin-derived DC cell line (XS52) but not by the other cell lines tested such as J774 MØ [2]. The proximal promoter of Dectin-2 was also suggested to support Langerhans-cell-specific gene expression [4]. Northern-blot analysis, however, showed that the highest levels of transcript were present in the spleen and thymus [2].…”

Section: Introductionmentioning

confidence: 99%

Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicitedin vivo

et al. 2005

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Dectin-2 is a recently described dendritic-cell-associated receptor, suggested to be involved in the initiation and maintenance of UV-induced tolerance. To understand the physiological relevance of the proposed functions of this C-type lectin-like receptor, we have generated monoclonal antibodies against its extracellular domain and performed a detailed study of its expression. In naive mice, Dectin-2 has a novel distribution pattern compared with other myeloid markers, but is predominantly expressed by a wide variety of tissue macrophages. Its expression was limited on dendritic cells and notably absent from brain microglia and choroid plexus or meningeal macrophages. On peripheral blood monocytes, Dectin-2 expression was very low on the surface but was transiently and markedly up-regulated on induction of inflammation in vivo using a variety of stimuli. This change in Dectin-2 expression occurs on 'inflammatory' monocytes after arrival at the inflammatory lesion as demonstrated by adoptive cell-transfer studies, and is independent of whether the macrophages elicited by the stimuli ultimately expressed Dectin-2. These observations show Dectin-2 expression to be characteristic of monocyte activation/maturation at an inflammatory lesion and provide a new perspective on the interpretation of Dectin-2 function in vivo.

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“…Epidermal cells were isolated from ear skin of BALB/c mice using trypsin (Mediatech); LC were enriched by centrifugation over Histopaque (1.083, Sigma-Aldrich) (21). Bone marrow (BM) DC were harvested from day 6 culture of BM cells with GM-CSF (22).…”

Section: Preparation Of Apcmentioning

confidence: 99%

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

Chung

Yudate

Tomihari

et al. 2009

The Journal of Immunology

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APCs express receptors recognizing microbes and regulating immune responses by binding to corresponding ligands on immune cells. Having discovered a novel inhibitory pathway triggered by ligation of DC-HIL on APC to a heparin/heparan sulfate-like saccharide of syndecan-4 on activated T cells, we posited DC-HIL can recognize microbial pathogens in a similar manner. We showed soluble recombinant DC-HIL to bind the dermatophytes Trichophyton rubrum and Microsporum audouinii, but not several bacteria nor Candida albicans. Dermatophyte binding was inhibited completely by the addition of heparin. Because DC-HIL contains an ITAM-like intracellular sequence, we questioned whether its binding to dermatophytes can induce tyrosine phosphorylation in dendritic cells (DC). Culturing DC with T. rubrum (but not with C. albicans pseudohyphae) induced phosphorylation of DC-HIL, but not when the tyrosine residue of the ITAM-like sequence was mutated to phenylalanine. To examine the functional significance of such signaling on DC, we cross-linked DC-HIL with mAb (surrogate ligand), which not only induced tyrosine phosphorylation but also up-regulated expression of 23 genes among 662 genes analyzed by gene-array, including genes for profilin-1, myristoylated alanine rich protein kinase C substrate like-1, C/EBP, LOX-1, IL-1β, and TNF-α. This cross-linking also up-regulated expression of the activation markers CD80/CD86 and heightened APC capacity of DC to activate syngeneic T cells. Our findings support a dual role for DC-HIL: inhibition of adaptive immunity following ligation of syndecan-4 on activated T cells and induction of innate immunity against dermatophytic fungi.

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Epidermal Langerhans Cell-Targeted Gene Expression by a Dectin-2 Promoter

Cited by 43 publications

References 50 publications

Targeting dendritic cells with antigen via dendritic cell-associated promoters

Targeting dendritic cells with antigen via dendritic cell-associated promoters

Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicitedin vivo

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

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