Distinct dendritic cell subsets differentially regulate the class of immune response<i>in</i><i>vivo</i>

Pulendran, Bali; Smith, Jeffrey L.; Caspary, G.; Brasel, Kenneth; Pettit, Dean K.; Maraskovsky, Eugene; Maliszewski, Charles R.

doi:10.1073/pnas.96.3.1036

Cited by 920 publications

(749 citation statements)

References 37 publications

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“…The splenic DC preparation also consisted of about 5% plasmacytoid DC, which were CD11c int , I-Ab -/low and mouse plasmacytoid DC antigen 1 (m-PDCA-1) + . Splenic OT-I CD8 T cells that were freshly isolated or pre-activated with PMA and ionomycin for 2 days were cultured with splenic DC pulsed with either relevant peptide OVA 257-264 or control peptide GP [33][34][35][36][37][38][39][40][41] . After 20 h of co-culture, the expression of CD40, CD80 and CD86 on DC was determined by flow cytometry.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2008

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“…By contrast, DCs from wild-type mice release lower amounts of IL-12 and have the capacity to promote IFN-γ and IL-4 production upon adoptive transfer. We next compared the number of CD8α + and CD8α − DCs in wild-type and μMT mice, since only the subset of DCs expressing CD8α has been shown to produce IL-12 18 19. The data in Table show that the proportion of DC subsets is similar in both strains of mice.…”

Section: Resultsmentioning

confidence: 99%

“…We and others have reported that subclasses of DCs directed the development of distinct T helper cells in vivo 18 19. Thus, CD8α + and CD8α − DCs, purified from spleens, have the potential to differentially regulate the Th1/Th2 balance: CD8α − DCs induced the activation of cells secreting high levels of IL-4, IL-5, and IL-10, and low levels of IL-2 and IFN-γ, whereas CD8α + DCs sensitize cells producing IL-2 and IFN-γ, but little IL-4, IL-5, or IL-10.…”

Section: Discussionmentioning

confidence: 96%

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Moulin

Andris

Thielemans

et al. 2000

The Journal of Experimental Medicine

234

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Increasing evidence indicates that dendritic cells (DCs) are the antigen-presenting cells of the primary immune response. However, several reports suggest that B lymphocytes could be required for optimal T cell sensitization. We compared the immune responses of wild-type and B cell-deficient (μMT) mice, induced by antigen emulsified in adjuvant or pulsed on splenic dendritic cells. Our data show that lymph node cells from both control and μMT animals were primed, but each released distinct cytokine profiles. Lymph node T cells from control animals secreted interferon (IFN)-γ, interleukin (IL)-2, and IL-4, whereas those from μMT mice produced IFN-γ and IL-2 but no IL-4. To test whether B cells may influence the T helper cell type 1 (Th1)/Th2 balance by affecting the function of DCs, we immunized mice by transferring antigen-pulsed DCs from wild-type or mutant mice. Injection of control DCs induced the secretion of IL-4, IFN-γ, and IL-2, whereas administration of DCs from μMT animals failed to sensitize cells to produce IL-4. Analysis of IL-12 production revealed that DCs from μMT mice produce higher levels of IL-12p70 than do DCs from wild-type animals. These data suggest that B lymphocytes regulate the capacity of DCs to promote IL-4 secretion, possibly by downregulating their secretion of IL-12, thereby favoring the induction of a nonpolarized immune response.

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“…Tip-DCs develop later during infection from recruited monocytes and by GM-CSF secreted from T cells at the site of inflammation. Others reported that the steady-state occurring splenic DC subsets (CD8a À , CD8a 1 or plasmacytoid DCs) show intrinsic differences to mount preferentially a Th1-or Th2-cell biased response [8,55,56]. Thus, our BM-DC equivalents to Tip-DCs might play a decisive role in dampening or modulating the initially mounted Th-cell response to effectively eliminate the invading pathogen, a process also referred to as ''success-driven'' Th-cell modulation [57].…”

Section: Discussionmentioning

confidence: 99%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

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Distinct dendritic cell subsets differentially regulate the class of immune responseinvivo

Cited by 920 publications

References 37 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

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

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Distinct dendritic cell subsets differentially regulate the class of immune responseinvivo

Cited by 920 publications

References 37 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

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

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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