Dermal IRF4+ dendritic cells and monocytes license CD4+ T helper cells to distinct cytokine profiles

Abstract Antigen (Ag)-presenting cells (APC) instruct CD4+ helper T (Th) cell responses, but it is unclear whether different APC subsets contribute uniquely in determining Th differentiation in pathogen-specific settings. Here, we use skin-relevant, fluorescently-labeled bacterial, helminth or fungal pathogens to track and characterize the APC populations that drive Th responses in vivo. All pathogens are taken up by a population of IRF4+ dermal migratory dendritic cells (migDC2) that similarly upregulate surface co-stimulatory molecules but express pathogen-specific cytokine and chemokine transcripts. Depletion of migDC2 reduces the amount of Ag in lymph node and the development of IFNγ, IL-4 and IL-17A responses without gain of other cytokine responses. Ag+ monocytes are an essential source of IL-12 for both innate and adaptive IFNγ production, and inhibit follicular Th cell development. Our results thus suggest that Th cell differentiation does not require specialized APC subsets, but is driven by inducible and pathogen-specific transcriptional programs in Ag+ migDC2 and monocytes.

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Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand

Blood ◽

10.1182/blood-2004-10-3944 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3206-3213 ◽

Cited By ~ 77

Author(s):

Jens Dannull ◽

Smita Nair ◽

Zhen Su ◽

David Boczkowski ◽

Christian DeBeck ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Responses ◽

Human Monocyte ◽

Interleukin 12 ◽

T Helper ◽

Cell Responses ◽

Mrna Transfection

Abstract The objective of this study was to investigate whether the immunostimulatory properties of human monocyte-derived dendritic cells (DCs) could be enhanced by triggering OX40/OX40L signaling. Since monocyte-derived DCs possess only low-cell surface levels of OX40L in the absence of CD40 signaling, OX40L was expressed by transfection of DCs with the corresponding mRNA. We show that OX40L mRNA transfection effectively enhanced the immunostimulatory function of DCs at multiple levels: OX40L mRNA transfection augmented allogeneic and HLA class II epitope-specific CD4+ T-cell responses, improved the stimulation of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without interfering with the prostaglandin E2 (PGE2)–mediated migratory function of the DCs, and facilitated interleukin 12 p70 (IL-12p70)–independent T helper type 1 (Th1) polarization of naive CD4+ T-helper cells. Furthermore, vaccination of tumor-bearing mice using OX40L mRNA–cotransfected DCs resulted in significant enhancement of therapeutic antitumor immunity due to in vivo priming of Th1-type T-cell responses. Our data suggest that transfection of DCs with OX40L mRNA may represent a promising strategy that could be applied in clinical immunotherapy protocols, while circumventing the current unavailability of reagents facilitating OX40 ligation.

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TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand

Journal of Experimental Medicine ◽

10.1084/jem.20051135 ◽

2005 ◽

Vol 202 (9) ◽

pp. 1213-1223 ◽

Cited By ~ 696

Author(s):

Tomoki Ito ◽

Yui-Hsi Wang ◽

Omar Duramad ◽

Toshiyuki Hori ◽

Guy J. Delespesse ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Th2 Cells ◽

T Helper ◽

Cell Responses ◽

Th Cell ◽

Tnf Α ◽

Ox40 Ligand ◽

Helper Type

We recently showed that dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) prime naive CD4+ T cells to differentiate into T helper type 2 (Th2) cells that produced high amounts of tumor necrosis factor-α (TNF-α), but no interleukin (IL)-10. Here we report that TSLP induced human DCs to express OX40 ligand (OX40L) but not IL-12. TSLP-induced OX40L on DCs was required for triggering naive CD4+ T cells to produce IL-4, -5, and -13. We further revealed the following three novel functional properties of OX40L: (a) OX40L selectively promoted TNF-α, but inhibited IL-10 production in developing Th2 cells; (b) OX40L lost the ability to polarize Th2 cells in the presence of IL-12; and (c) OX40L exacerbated IL-12–induced Th1 cell inflammation by promoting TNF-α, while inhibiting IL-10. We conclude that OX40L on TSLP-activated DCs triggers Th2 cell polarization in the absence of IL-12, and propose that OX40L can switch IL-10–producing regulatory Th cell responses into TNF-α–producing inflammatory Th cell responses.

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CD8− DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS

Journal of Experimental Medicine ◽

10.1084/jem.20062305 ◽

2007 ◽

Vol 204 (7) ◽

pp. 1525-1531 ◽

Cited By ~ 126

Author(s):

Dimitris Skokos ◽

Michel C. Nussenzweig

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Toll Like Receptor ◽

T Helper ◽

Cell Responses ◽

Ligand Expression ◽

Th 1 ◽

Dependent Mechanism

Toll-like receptor (TLR) ligation is believed to skew T cell responses toward T helper (Th)1 differentiation by inducing interleukin (IL)-12 secretion by CD8+ dendritic cells (DCs). However, TLR-dependent Th1 responses occur in the absence of IL-12. To determine how DCs induce Th1 differentiation in the absence of IL-12, we examined the response of IL-12–deficient DCs to bacterial lipopolysaccharide (LPS). We find that LPS activates MyD88-dependent Delta 4 Notch-like ligand expression by CD8− DCs, and that these cells direct Th1 differentiation by an IL-12–independent and Notch-dependent mechanism in vitro and in vivo. Thus, activation of the two DC subsets by TLR4 leads to Th1 responses by two distinct MyD88-dependent pathways.

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