T-cell priming by type-1and type-2 polarized dendritic cells: the concept of a third signal

Kaliński, Paweł; Hilkens, Catharien M. U.; Wierenga, Eddy A.; Kapsenberg, Martien L.

doi:10.1016/s0167-5699(99)01547-9

Cited by 822 publications

(717 citation statements)

References 79 publications

Supporting

Mentioning

679

Contrasting

Unclassified

Order By: Relevance

“…In our recent studies, we observed that strong IDO induction as a counterregulatory mechanism mediated APC activation [6,15], particularly when DCs were polarized by IFN-γ toward a DC1 phenotype [30,31]. Here, consistent with previous literature [25,26], we found that the cytokine and PGE 2 -matured DCs failed to produce the key cytokines characterizing a DC1 phenotype IL12p70 and IFN-γ [30,32] (Fig.…”

Section: Pge2 Stimulates DC Ido Competence But Not Proinflammatory Cysupporting

confidence: 91%

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

et al. 2012

View full text Add to dashboard Cite

Prostaglandin E2 (PGE 2 ), an abundantly produced lipid messenger in mammalian organisms, has been attributed to possess potent albeit ambivalent immunological functions. Recently, PGE 2 has been reported to stimulate the commonly believed immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway in human dendritic cells (DCs), but without promoting DC immunosuppressive activity. Here, we report that PGE 2 used as a DC maturation agent apparently has more diverse functions. PGE 2 -matured DCs acquired powerful IDO activity, which was sustained even after removing PGE 2 . These IDO-competent DCs were able to stimulate allogeneic T-cell proliferation, but achieved inhibitory activity as their content in DC/T-cell co-cultures increased. The DC inhibitory activity was reversed upon blockade of IDO activity, confirming that the suppressive effect was in fact mediated by IDO and occurred in a dose-dependent fashion. IDO-mediated T-cell suppression was restored upon re-stimulation of T cells in the absence of IDO activity, confirming its reversibility. T cells stimulated by PGE 2 -matured IDO-competent DCs were sensitized to produce multiple cytokines, comprising Th1, Th2, and Th17 phenotypes. Collectively, these data suggest that T cells stimulated by PGE 2 -matured DCs are not terminally differentiated and their ultimate type of response may be formed by microenvironmental conditions. Keywords: Human dendritic cells r IL-23 r Immunosuppression r Indoleamine 2,3-dioxygenase (IDO) r Prostaglandin E2 Supporting Information available online IntroductionThe intracellular enzyme indoleamine 2,3-dioxygenase (IDO) has a key function in tryptophan metabolism along the kynurenine pathway [1]. IDO's metabolic activity has been perceived to play a significant role in immune regulation. On the cellular level, the complementary effects of IDO-mediated metabolism, tryptophan starvation, and accumulation of immunomodulatory kynurenines Correspondence: Dr. Andreas Heitger e-mail: andreas.heitger@ccri.at at the antigen-presenting cell (APC)/T-cell synapse were proposed to effect regulation of T-cell activation and proliferation [1,2]. In fact, in the last decade, multiple studies corroborated the role of IDO in immune regulation and induction of tolerance (reviewed in [3,4]). IDO competence, i.e. IDO expression and activity [5,6], has been suggested to play a critical role in numerous clinical conditions entailing immune regulation, including tolerance induction in pregnancy [7], transplantation [8,9], and tumor immune evasion [10]. * These authors contributed equally to the work. Eur. J. Immunol. 2012Immunol. . 42: 1117Immunol. -1128 Effective induction of IDO competence is, by and large, restricted to cells of the monocyte/macrophage lineage and, in humans is predominantly found in dendritic cells (DCs) [4,11]. Numerous agents, most prominently interferon (IFN)-γ, have been described to induce IDO activity in DCs [12]. IDO induction is generally believed to represent a feedback mechanism of APC activation [8]. This understanding...

show abstract

Section: Pge2 Stimulates DC Ido Competence But Not Proinflammatory Cysupporting

confidence: 91%

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The capacity of DCs to direct the development of selected Th populations has been shown to be modulated by pathogens, cytokines, and other environmental factors 2. In particular, we have shown that DCs may induce the development of Th0 (or Th1 and Th2) lymphocytes in a neutral environment, and the differentiation of a polarized Th1 or Th2 population in the presence of IL-12 or IL-10, respectively 3.…”

Section: Introductionmentioning

confidence: 85%

B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo

Moulin

Andris

Thielemans

et al. 2000

The Journal of Experimental Medicine

234

View full text Add to dashboard Cite

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.

show abstract

“…DCs 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].…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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...

show abstract

T-cell priming by type-1and type-2 polarized dendritic cells: the concept of a third signal

Cited by 822 publications

References 79 publications

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

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

Contact Info

Product

Resources

About