CD40 Triggering of Heterodimeric IL-12 p70 Production by Dendritic Cells In Vivo Requires a Microbial Priming Signal

Schulz, Oliver; Edwards, Alexander D.; Schito, Marco; Aliberti, Júlio; Manickasingham, Shivanthi P.; Sher, Alan; Sousa, Caetano Reis e

doi:10.1016/s1074-7613(00)00045-5

Cited by 516 publications

(473 citation statements)

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“…2B). Since IL-12p70 production requires at least two activating signals for DC [16,24,25], we included LPS in the co-cultures to provide the additional stimulus. We found that this had an additive effect on the levels of IL-12p40 produced, but IL-12p70 levels remained barely detectable (<20 pg/mL) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CD40-CD40L interaction is essential for CD8 T cellmediated IL-12p70 production CD40 stimulation is important for IL-12p70 production by DC [25,29,30]. To investigate whether CD40-CD40L interactions were involved in our system, we obtained DC from CD40 -/-mice for coculture with activated CD8 T cells and LPS (Fig.…”

Section: Cd8 T Cell-mediated Il-12p70 Production Is Contact-dependentmentioning

confidence: 99%

“…Data are representative of at least three independent experiments and shown as mean AE SD. IFN-c and other CD8 T cell-derived soluble factors were insufficient to prime DC for IL-12p70, and that additional mechanisms mediated through cell-cell contact were necessary for CD8 T cell-mediated IL-12p70 production.CD40-CD40L interaction is essential for CD8 T cellmediated IL-12p70 production CD40 stimulation is important for IL-12p70 production by DC [25,29,30]. To investigate whether CD40-CD40L interactions were involved in our system, we obtained DC from CD40 -/-mice for coculture with activated CD8 T cells and LPS (Fig.…”

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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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Section: Resultsmentioning

confidence: 99%

Section: Cd8 T Cell-mediated Il-12p70 Production Is Contact-dependentmentioning

confidence: 99%

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

et al. 2008

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“…2 Thus, IL-12 is secreted as an early pro-inflammatory cytokine in response to infections. 3 Additional amplifying signals such as interferon-g (IFN-g), 4 IL-15 5 or cluster of differentiation (CD)40L-CD40 cell-cell interactions 6 are necessary for the optimal production of biologically active IL-12. Conversely, IL-12 is negatively regulated through cytokines such as IL-10 and transforming growth factor-b1 (TGF-b1).…”

Section: Open Questionsmentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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“…In addition, molecules derived from bacterial or viral products, as well as pro-inflammatory cytokines (TNFα and IFNγ) and T cell signals such as CD40-ligand (CD40L), can promote the secretion of IL-12p70 and TNFα from DC thereby promoting a Th1-skewed response (Schulz et al, 2000;Vieira et al, 2000). In contrast, anti-inflammatory molecules such as IL-10, prostaglandin E2 (PGE2) and corticosteroids can inhibit RTDC maturation and cytokine production and therefore promote a Th2-skewed response (Kalinski et al, 1997;Faries et al, 2001;Kalinski et al, 2001).…”

Section: Peripheral T Cell Regulationmentioning

confidence: 99%

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

Burchell

Strickland

Stumbles

2010

Pharmacology & Therapeutics

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Airways hyperresponsiveness (AHR) is one of the major clinical features of allergic airways disease including allergic asthma, however the immunological mechanisms leading to the induction and regulation of this disorder are not fully understood. In this review we will summarise the evidence of a number of studies, principally in murine models of AHR, suggesting a central role for respiratory tract dendritic cells (RTDC) in the induction of AHR through the generation of lung-homing, allergen-specific effector T cells. We will also summarise the evidence supporting a role for regulatory T cells in the attenuation of AHR and will propose that, as a counterpoint to their capacity to induce AHR, RTDC may also play a role in the attenuation of AHR through the generation of regulatory T cells (Treg). A better understanding of the relationship between the physiological and immunological responses to allergen-induced AHR attenuation, and particularly the role of RTDC and Treg in this process, will be essential for the development of new treatments and therapies.

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CD40 Triggering of Heterodimeric IL-12 p70 Production by Dendritic Cells In Vivo Requires a Microbial Priming Signal

Cited by 516 publications

References 42 publications

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

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

New insights into IL-12-mediated tumor suppression

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

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CD40 Triggering of Heterodimeric IL-12 p70 Production by Dendritic Cells In Vivo Requires a Microbial Priming Signal

Cited by 516 publications

References 42 publications

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

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

New insights into IL-12-mediated tumor suppression

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

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

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