Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

Hochrein, Hubertus; O’Keeffe, Meredith; Luft, Thomas; Vandenabeele, Stéphane; Grumont, Raelene J.; Maraskovsky, Eugene; Shortman, Ken

doi:10.1084/jem.192.6.823

Cited by 334 publications

(298 citation statements)

References 55 publications

Supporting

Mentioning

268

Contrasting

Unclassified

Order By: Relevance

“…In contrast, it has been reported previously that CD8 T cell-mediated IL-12p70 production could occur without stimulation from pathogenderived signals [11,14,15]. A possible reason is that GM-CSFand IL-4-generated DC used in those studies have a greater propensity to produce IL-12p70 than splenic DC [27,29]. We argue that our study better reflects events that may occur with splenic resident DC in vivo.…”

Section: Discussionmentioning

confidence: 63%

“…IFN-c, GM-CSF, TNF-a and IL-4 are T cell-derived cytokines thought to be involved in promoting IL-12p70 production by DC [14,15,[26][27][28]. We investigated whether these factors were involved in our system.…”

Section: Cd8 T Cell-mediated Il-12p70 Production Is Dependent On Ifn-cmentioning

confidence: 99%

“…Increasing the CD8 T cell-to-DC ratio in culture proportionately increased the amount of IL-12p70 produced by DC. These results indicate that CD8 T cell priming of DC for IL-12p70 was MHC class I-peptide (K b /OVA 257-264 )-specific and CD8 T cell-dependent.CD8 T cell-mediated IL-12p70 production is dependent on IFN-c IFN-c, GM-CSF, TNF-a and IL-4 are T cell-derived cytokines thought to be involved in promoting IL-12p70 production by DC [14,15,[26][27][28]. We investigated whether these factors were involved in our system.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2008

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Cd8 T Cell-mediated Il-12p70 Production Is Dependent On Ifn-cmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2008

View full text Add to dashboard Cite

show abstract

“…9,10 IL-4 can enhance the production of IL-12 by DC and has been confirmed to play roles in the antitumor response. 8,11 Immature DC undergo a maturation process after they encounter antigens, and subsequently migrate to lymphoid tissue to prime naive T cells. 12,13 Induction of effective antitumor response requires DC to present tumor antigen, 14 but tumor cells often have limited expression of MHC antigens and costimulatory molecules, [15][16][17] and also tumor cells can produce immune inhibitory factors that inhibit DC maturation and migration.…”

Section: Activated DC To Produce High Levels Of Il-12 Furthermore Amentioning

confidence: 99%

Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

et al. 2002

View full text Add to dashboard Cite

“…Sideby-side comparisons concluded that GM-CSF mainly differentiates monocyte-derived DCs and Flt3L differentiates the equivalents of resident CD8 1 DCs [16]. Although exogenous GM-CSF seems dispensable for the development of CD8 1 DCs [16], GM-CSF has been used in the cultures of resident DCs including CD8 1 DCs for functional assays to promote DC survival [17]. It was not known whether GM-CSF is required for the potentiation of function of CD8 1 DCs in vivo; nor what the molecular target of GM-CSF is.…”

Section: Introductionmentioning

confidence: 99%

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

et al. 2011

View full text Add to dashboard Cite

Resident CD8 1 DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8 1 DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L. monocytogenes by resident CD8 1 DCs. This previously unrecognized functional enhancement of CD8 1 DCs by GM-CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM-CSF was also marked by CD103 expression on CD8 1 DCs that was strongly regulated by GM-CSF. Our findings not only identify GM-CSF as a key molecule regulating CD8 1 DC function, but also as a factor responsible for functional heterogeneity of CD8 1 DCs that is at least substantially demarcated by CD103 expression.Keywords: CD8 1 DC . CD103 . Cross-presentation . Granulocyte-macrophage colony-stimulating factor . Listeria monocytogenes Supporting Information available online IntroductionDCs found in the spleen can be grossly separated into CD8 1 DCs and CD8 À DCs. The latter includes CD8 À CD4 1 and CD8 À CD4 À conventional DCs and CD45RA 1 plasmacytoid DCs. Different DC subsets have different functions. Notably, the resident CD8 1 DCs show superior capacity for ingesting cell-associated antigens [1], for cross-presenting antigens (i.e. presenting exogenous antigens to CD8 1 T cells) [2][3][4], for the rapid uptake of certain bacterial pathogens [5] and for producing . It has been previously reported that a small proportion of CD8 1 DCs express the integrin CD103 and these CD103-expressing CD8 1 DCs are enriched in cells engulfing cellular antigens and cross-priming CD8 1 T cells [7]. However, it is unclear what regulates the above Ã Co-senior authors. Here, we investigated whether GM-CSF might influence the function of CD8 1 DCs and CD103 expression. Functionally, DCs from GM-CSF transgenic (GMtg) mice had enhanced crosspresentation, whereas in the absence of GM-CSF signaling, crosspresentation was reduced. Rapid uptake of Listeria monocytogenes by CD8 1 DCs was also reduced in the absence of GM-CSF. Phenotypically, we showed that bacterial infection preferentially increased CD103 expression by CD8 1 DCs and this increase was dependent on GM-CSF. Together, our results identify a critical role for GM-CSF in preferentially regulating expression of the integrin CD103 by CD8 1 DCs and in regulating certain functions of CD8 1 DCs. ResultsGM-CSF enhances cross-presentation by CD8 1 DCs GM-CSF is a cytokine that exists at very low levels at steady state but is greatly induced during infection and inflammation [13]. To understand the role of GM-CSF in regulating the functions of CD8 1 DCs, we chose mouse models with GM-CSF overexpression. We first compared the cross-presentation by CD8 1 DCs from GMtg mice and control littermates. When soluble OVA was used as the antigen in vitro, CD...

show abstract

Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

Cited by 334 publications

References 55 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

Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

Contact Info

Product

Resources

About

Interleukin (Il)-4 Is a Major Regulatory Cytokine Governing Bioactive IL-12 Production by Mouse and Human Dendritic Cells

Cited by 334 publications

References 55 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

Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8+ spleen dendritic cells

Contact Info

Product

Resources

About

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

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

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells