Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system.

Hsieh, Chyi-Song; Heimberger, Amy B.; Gold, Jennifer S.; O’Garra, Anne; Murphy, Kenneth M.

doi:10.1073/pnas.89.13.6065

Cited by 653 publications

(448 citation statements)

References 49 publications

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“…A similar observation was made with CD40 ligand-stimulated murine dendritic cell-containing populations by Takenaka et al (43). IFN-␥ appears not to mediate the IL-4 effect, because its production was not induced by IL-4 in our hands, and moreover, IL-4 has typically been described to inhibit IFN-␥ rather than enhancing it (44,45). In addition, neutralization of IFN-␥ in the stimulation assays did not prevent the IL-4-induced increase in IL-12 production.…”

Section: Augmenting Effects Of Il-4: Mechanismsupporting

confidence: 56%

Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4

Ebner¹,

Ratzinger²,

Krösbacher³

et al. 2001

The Journal of Immunology

143

104

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Dendritic cells produce IL-12 both in response to microbial stimuli and to T cells, and can thus skew T cell reactivity toward a Th1 pattern. We investigated the capacity of dendritic cells to elaborate IL-12 with special regard to their state of maturation, different maturation stimuli, and its regulation by Th1/Th2-influencing cytokines. Monocyte-derived dendritic cells were generated with GM-CSF and IL-4 for 7 days, followed by another 3 days ± monocyte-conditioned media, yielding mature (CD83+/dendritic cell-lysosome-associated membrane glycoprotein+) and immature (CD83−/dendritic cell-lysosome-associated membrane glycoprotein−) dendritic cells. These dendritic cells were stimulated for another 48 h, and IL-12 p70 was measured by ELISA. We found the following: 1) Immature dendritic cells stimulated with CD154/CD40 ligand or bacteria (both of which concurrently also induced maturation) secreted always more IL-12 than already mature dendritic cells. Mature CD154-stimulated dendritic cells still made significant levels (up to 4 ng/ml). 2) Terminally mature skin-derived dendritic cells did not make any IL-12 in response to these stimuli. 3) Appropriate maturation stimuli are required for IL-12 production: CD40 ligation and bacteria are sufficient; monocyte-conditioned media are not. 4) Unexpectedly, IL-4 markedly increased the amount of IL-12 produced by both immature and mature dendritic cells, when present during stimulation. 5) IL-10 inhibited the production of IL-12. Our results, employing a cell culture system that is now being widely used in immunotherapy, extend prior data that IL-12 is produced most abundantly by dendritic cells that are beginning to respond to maturation stimuli. Surprisingly, IL-12 is only elicited by select maturation stimuli, but can be markedly enhanced by the addition of the Th2 cytokine, IL-4.

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Section: Augmenting Effects Of Il-4: Mechanismsupporting

confidence: 56%

Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4

Ebner¹,

Ratzinger²,

Krösbacher³

et al. 2001

The Journal of Immunology

143

104

View full text Add to dashboard Cite

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“…In addition, the availability of co-stimulatory signals in the microenvironment (e.g. , cytokines) may influence the nature of the T cell immune response [37].…”

Section: Discussionmentioning

confidence: 99%

Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation to antigen‐specific T cells

et al. 1993

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Murine epidermal Langerhans cells (LC) have been shown to internalizeLeishmania major, a cause of human cutaneous leishmaniasis, and to stimulate a vigorous parasite-specific T cell response. The present study emphasizes the critical role of LC in leishmaniasis by documenting directly that LC have the ability to transport L. major from the skin to the draining lymph node (LN). This was revealed by irreversible labeling of LC with a fluorescent cell linker and in vivo tracking. In contrast, no migration to the LN was seen with L. majorinfected macrophages. These findings were consistent with the results of mixed labeling immunohistology showing that early in infection the expression of parasite antigen in the LN draining the lesion was confined to dendritic cells and could not be detected in macrophages. Furthermore, dendritic cells in LN draining the site of cutaneous infection stimulated L. major-primed T cells in vitro and, most notably, were able to activate unprimed T cells capable of mediating parasite-specific delayed-type hypersensitivity reactivity in vivo . Taken together, the results indicate that LC capture L. major in the skin and transport it to the regional LN for initiation of the specific T cell immune response.

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“…APCs are thought to modulate the cytokine differentiation of T cells via the secretion of IL-12 to induce Th1 cells, or IL-4 and IL-6 to promote Th2 responses [2,3]. Interestingly, immunologic adjuvants, such as complete Freunds' adjuvant (CFA; mineral oil containing inactivated mycobacteria), activate APCs and modulate the cytokine differentiation of the ensuing T cell response.…”

Section: Introductionmentioning

confidence: 99%

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

Denkinger

Forsthuber

2007

Cellular Immunology

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Pertussis toxin (PTX) has potent immunologic adjuvant activity in vivo and concomitantly enhances both T helper type (Th) 1 and Th2 cytokine responses. The PTX-induced enhancement of Th1 and Th2 immunity is mediated via the activation of antigen presenting cells (APCs), but the underlying mechanism is not known.Here we asked whether the adjuvant activity of PTX on T cell immunity was mediated by cytokines and/or costimulatory signals.The results show that in vivo blockade of CD28-CD80/86 costimulation essentially abrogated PTXmediated enhancement of antigen-specific Th1 and Th2 responses. Blockade of CD40L-CD40 interactions was less efficient in inhibiting PTX-mediated enhancement of Th1 and Th2 responses. In contrast, the adjuvant activity of PTX was not mediated via cytokines, because neither Th1 nor Th2 responses were substantially impaired in mice deficient for IL-12, IFN-γ, IL-4, IL-5, or IL-6.Collectively, the data suggest that PTX mediates its adjuvant effects on T cell cytokine differentiation and clonal expansion via the modulation of costimulatory molecules on APCs. Understanding the costimulatory pathways targeted by PTX could lead to the design of novel adjuvants that selectively induce Th1 or Th2 immunity.

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Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system.

Cited by 653 publications

References 49 publications

Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4

Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4

Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation to antigen‐specific T cells

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

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