Toll‐like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α<sup>+</sup> DC correlates with unresponsiveness to imidazoquinolines

Edwards, Alexander D.; Diebold, Sandra S.; Slack, Emma; Tomizawa, Hideyuki; Hemmi, Hiroaki; Kaisho, Tsuneyasu; Akira, Shizuo; Sousa, Caetano Reis e

doi:10.1002/eji.200323797

Cited by 501 publications

(478 citation statements)

References 30 publications

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“…Our observation is in accordance with several studies showing that CpG-activated DC are potent inducers of immune responses against intracellular pathogens in vivo [41,42]. It is not clear why the effect of CpG is much more potent on CD8 + DC, since both CD8 + and CD8 -DC express TLR9 and up-regulate costimulatory molecules to the same extent ( [43] and data not shown). However, the dramatic effect of CpG on IFN-c production by the responding CD4 T cells can be explained by the exceptional capacity of CD8 + DC to produce IL-12p70 in response to this stimulus [24][25][26].…”

Section: Discussionsupporting

confidence: 92%

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

et al. 2005

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Freshly isolated quiescent splenic dendritic cell (DC) subtypes differ in their capacity to activate naive CD4 T cells in culture. The CD8 + DC showed a reduced capacity to stimulate T cell proliferation compared to either of the CD8 -DC subsets, regardless of antigen and DC dose. In contrast to CD8 -DC, the quiescent CD8 + DC did not induce IFN-c production from CD4 T cells. The difference between the DC subtypes appeared to be at the level of initial surface molecule interactions, but could not be attributed to differences in expression of MHC class II or B7 family molecules, or to the expression of Fas ligand on DC. However, when activated by inclusion of the Toll-like receptor 9 ligand CpG in culture, CD8 + DC became potent stimulators of both CD4 T cell proliferation and IFN-c production. In contrast, similar activation of CD8 -DC produced a more modest increase in capacity to stimulate CD4 T cell proliferation and no increase in capacity to stimulate IFN-c production. The difference between a quiescent and an activated state is therefore more extreme for CD8 + than for CD8 -DC. The especially tight regulation of the activity of CD8 + DC may be essential for the maintenance of self tolerance.

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Section: Discussionsupporting

confidence: 92%

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

et al. 2005

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“…The subset-specific lack of TLR7/8 expres-sion could be important for tolerance to self antigens, as the CD172a low iL-DC lacking TLR7 and 8 expression will be less likely to respond to their cargo of cellular debris, which includes ssRNA. That this could be important for self tolerance is supported by murine studies showing that CD8a + DC, which share the selective ability to take up dying cells in vivo [2,3], do not express TLR7, whereas CD8a -DC do [16].…”

Section: Discussionmentioning

confidence: 96%

“…For example, murine DC subsets differentially express TLR7, and these expression patterns may result in subset-dependent responses after i.v. administration of TLR7/8 ligands such as the synthetic adjuvant resiquimod (R-848) [15,16]. With respect to migrating DC, especially their subsets, very little is known about expression of TLR and their response to specific TLR ligands in vivo.…”

Section: Introductionmentioning

confidence: 99%

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

Yrlid¹,

Cerovic

Milling³

et al. 2006

Eur J Immunol

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The intestinal innate immune system continually interacts with commensal bacteria, thus oral vaccines should induce extra/alternative activation of DC, potentially through TLR. To examine this we collected intestinal lymph DC (iL-DC) under steady-state conditions and after feeding resiquimod (R-848), a synthetic TLR7/8 ligand, which we showed induces complete emptying of gut DC into lymph. iL-DC are heterogeneous with subset-specific functions. In this study we determined the kinetics of iL-DC subset release, activation and cytokine secretion induced by R-848. We show that L-DC comprise three distinct subsets (CD172a high , CD172a int and CD172a low ) present with similar frequencies in intestinal but not hepatic lymph. No iL-DC express TLR7 mRNA, and only CD172a + iL-DC express TLR8. However, after oral R-848 administration, output of all three subsets increases dramatically. CD172a high DC release precedes that of CD172a low DC, and the increased frequency of CD25 high iL-DC is restricted to the two CD172a + subsets. After feeding R-848 only CD172a high iL-DC secrete IL-6 and IL-12p40. However, CD172a int and CD172a high DC secrete similar but markedly lower amounts when stimulated in vitro. These results highlight the importance of in vivo approaches to assess adjuvant effects on DC and give novel insights into the subset-specific effects of an oral TLR ligand on intestinal DC.

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“…Furthermore, CD8a + DC are specialized in cross-priming CD8 T cell responses [35][36][37][38][39][40][41][42]. In contrast, other reports have shown that IL-12 can also be produced by CD8a -DC [43,44].To determine whether IL-12p70 production was restricted to the CD8a + DC subset in this study, we sorted splenic DC according to the expression of CD8a prior to peptide pulsing and co-culture with CD8 T cells. IL-12p70 was detected with unsorted DC and CD8a + DC, but not the CD8a -DC (Fig.…”

mentioning

confidence: 99%

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

et al. 2008

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CD8a + DC are implicated as the principle DC subset for cross-presentation and crosspriming of cytotoxic CD8 T cell responses. In this study, we demonstrate another unique facet of the CD8a + DC and CD8 T cell relationship, by showing that CD8 T cells reciprocally activate CD8a + DC, but not CD8a -DC, for IL-12p70 production, the key Th1-promoting cytokine. This effect was observed during an antigen-specific interaction between DC and activated CD8 T cells, along with secondary TLR stimulation of DC by LPS. Activated CD8 T cells use a combination of IFN-c and CD40L, which is rapidly up-regulated poststimulation, to prime DC for IL-12p70 production during an antigen-specific response. Our results suggest that the interaction between CD8a + DC and antigen-primed CD8 T cells may form an important component of Th1-mediated immunity through the induction of IL-12p70. Key words: CD8 T cells Á Dendritic cells Á IL-12p70Introduction DC are essential for the activation and polarization of T cells during an adaptive immune response [1,2]. DC respond to stimulatory signals from microbes and inflammatory mediators and mature into professional antigen-presenting cells that prime the adaptive immune system [3,4]. DC activity is also influenced through direct and indirect interaction with other effector immune cells, which results in the delivery of "feedback" signals that can influence the activation status of the DC and thus the outcome of the adaptive immune response [5][6][7]. CD8 T cells are principally known for their role in cytotoxic killing. However, their ability to promote Th1 responses has also been described. In vivo, CD8 T cells have been shown to be essential for the induction of protective Th1 responses against microbial infections [8][9][10]. Likewise, CD8 T cells can also inhibit the development of allergic Th2 IgE responses [11,12]. CD8 T cells can have a direct impact on DC during their interaction, inducing DC to mature [13], and enhancing their Th1-polarizing capabilities by augmenting their ability to produce 14,15].IL-12p70 is a heterodimeric pro-inflammatory cytokine that plays a central role in Th1 immunity, acting on T cells and NK cells by inducing proliferation, cytotoxic function and IFN-c production [16]. IL-12p70 production by DC during T cell priming is crucial for the development of Th1 responses [16][17][18]. Hence, control of DC IL-12p70 production is important for the development of Th1 immunity.Previous reports on CD8 T cell-mediated IL-12p70 production utilized DC generated from monocytes or bone marrow progenitors using 14,15]. These DC are now thought to appear only under inflammatory conditions [19]. They differ markedly from DC that reside in lymphoid organs, and hence do not necessarily reflect events that occur with lymphoid resident DC. Splenic DC comprise of a heterogeneous population of cells with different phenotypes and functional characteristics [20]. It is unknown whether CD8 T cells could possibly modulate IL-12p70 production with splenic resident DC, or whether CD8 T cellme...

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Toll‐like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α⁺ DC correlates with unresponsiveness to imidazoquinolines

Cited by 501 publications

References 30 publications

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

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Toll‐like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines

Cited by 501 publications

References 30 publications

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

CD40L‐expressing CD8 T cells prime CD8α+ DC for IL‐12p70 production

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Toll‐like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α⁺ DC correlates with unresponsiveness to imidazoquinolines

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production