|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 90 No. 5 (September 1), 1997:
pp. 1920-1926
Human Dendritic Cells Require Exogenous Interleukin-12-Inducing Factors to Direct the Development of Naive T-Helper Cells Toward the Th1 Phenotype
By
Catharien M.U. Hilkens,
Pawel Kalinski,
Mark de Boer, and
Martien L. Kapsenberg
From Academic Medical Center, University of Amsterdam, Department of Cell Biology & Histology, Amsterdam; and PanGenetics, Amsterdam, The Netherlands.
 |
ABSTRACT |
Dendritic cells (DC) are important initiators of specific primary immune responses because they are the only APC that can efficiently activate naive Th cells. DC have the capacity to produce interleukin-12 (IL-12), a cytokine that plays a pivotal role in the development of Th1-mediated cellular immune responses. The present study focuses on the conditions under which human DC produce bioactive IL-12 p70 and, consequently, direct the development of naive T helper (Th) cells toward the Th1 phenotype. Bacteria or bacterial compounds such as Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS) induced substantial IL-12 levels in DC, which could be further upregulated by interferon- (IFN-), whereas induction of IL-12 production via CD40 ligation required IFN- as an obligatory, complementary signal. Also, activated naive Th cells were poor inducers of IL-12 production, unless exogenous IFN- was present, whereas activated memory Th cells were effective inducers of IL-12 production and did not require exogenous IFN-. Next, the cytokine profiles of matured Th cells that were primed by DC under different conditions were examined. DC promoted the development of naive Th cells into memory Th0 cells that produced both the type 1 cytokine IFN- and the type 2 cytokine IL-4. In contrast, after activation with SAC, DC efficiently directed the development of Th1 cells through the release of IL-12. An APC-independent Th cell maturation model, using either recombinant IL-12 or supernatants of SAC-activated DC and neutralizing anti-IL-12 antibodies, confirmed that DC-derived IL-12 was the major Th1 skewing factor. Together, these data indicate that the contact between DC and naive Th cells during the initiation of specific immune responses does not result in the efficient induction of IL-12 production and that, consequently, exogenous IL-12-inducing factors are required to promote primary Th1-mediated cellular immune responses.
| |
INTRODUCTION |
DENDRITIC CELLS (DC) are highly specialized antigen-presenting cells (APC) of the immune system.1 DC pick up and process antigen (Ag) with high efficiency in peripheral tissues and continuously migrate to lymphoid organs to present these Ag to specific T cells. In contrast to other types of APC, DC are potent activators of naive T cells and are, therefore, regarded as important initiators of primary specific immune responses.
The differential development of naive T helper (Th) cells into functionally distinct memory Th cells, such as Th type 1 (Th1) and Th2 cells, depends upon microenvironmental factors that are present at the time of T-cell activation. A powerful factor in this respect is interleukin-12 (IL-12), that strongly augments interferon- (IFN-) production by activated naive T cells and, therefore, skews their development toward the memory Th1 phenotype.2-4 Recently, it was shown that spleen- and skin-derived DC, as well as in vitro matured DC all have the capacity to produce IL-125-8 and it was, therefore, proposed that DC preferentially induce Th1 responses.5,6,8
It is well-documented that Th1 cells are required to generate protective, cell-mediated inflammatory responses against invading microorganisms, such as Leishmania major, Mycobacterium leprae, or Toxoplasma gondii.9-11 In other cases, however, Th1 cell-mediated responses may be disadvantageous, for instance in case of infection with certain nematode species of which the expelling requires strong Th2 responses.12 Moreover, Th1 cells may even play a pathogenic role, for instance in certain autoimmune diseases.13 Therefore, the concept that DC preferentially promote Th1 responses is rather unsatisfying. Because it is important that the development of Th1 responses does not occur via a default differentiation pathway, but can be selected when necessary, DC should produce physiologically significant IL-12 levels only when Th1 cell-mediated responses are beneficial.
In the present in vitro study, we examined the conditions under which human DC produce IL-12 and, consequently, skew naive Th cell responses toward the Th1 phenotype. For this purpose, we used CD1+ DC derived from peripheral blood precursors. As described previously,14,15 such cells fit the definition of DC based on (1) their typical dendritic morphology, (2) their high surface expression of CD1, major histocompatibility complex (MHC) II, and costimulatory molecules such as CD80 (B7.1) and CD86 (B7.2), (3) their high stimulatory capacity for naive T cells and, as mentioned before, (4) their potency to produce IL-12.
Here, we show that DC do not exert a Th1-promoting activity during the process of naive Th cell activation, because naive Th cells are poor inducers of IL-12 production. Only if DC are activated by exogenous IL-12-inducing factors such as bacteria or their constituents, they direct Th1 development through the release of IL-12.
| |
MATERIALS AND METHODS |
Antibodies and cytokines.
T cells were stimulated using CD3 monoclonal antibody (MoAb) (CLB-T3/3) and CD28 MoAb (CLB-CD28/1), all obtained from the Central Laboratory of The Netherlands Red Cross Blood Transfusion Service (CLB) (Amsterdam, The Netherlands). Fluorescence-activated cell sorting (FACS) analysis was performed using MoAbs against the following surface markers: CD1a (OKT6; Ortho Diagnostic Systems, Beerse, Belgium), CD4 (OKT4; Ortho), CD14 (Leu M3; Becton Dickinson, San Jose, CA), HLA-DR (L243; Becton Dickinson), CD80 (B7-24),16 and CD86 (1G10), both kindly provided by Innogenetics N.V., Ghent, Belgium, CD40 (EA-5; a gift from Dr T. LeBien, University of Minnesota, Minneapolis, MN), CD45RA (2H4; Coulter, Hialeah, FL) and CD45RO (UCHL-1; a gift from Dr P. Beverly, London, UK). Human rIL-12 (sp. act. 170 × 106 U/mg), neutralizing IL-12 goat antibodies and the IL-12 p70-specific MoAb 20C2 were gifts from Dr M.K. Gately (Hoffmann-La Roche, Nutley, NJ). The IL-12 p40-specific MoAb C8.6 was a gift from Dr G. Trinchieri (The Wistar Institute, Philadelphia, PA). Human rIL-2 was a gift from from Cetus Corp (Emeryville, CA; sp.act. 3 × 106 U/mg). Human rIL-4 (sp. act. 107 U/mg) was a gift from Dr J. E. de Vries (DNAX Research Institute, Palo Alto, CA). Human rIFN- (sp. act. 8 × 107 U/mg) was a gift from Dr. P. H. van der Meide (Biomedical Primate Research Center, Rijswijk, The Netherlands). Human rGM-CSF (sp. act. 11.1 × 106 U/mg) was obtained from Sandoz Pharma LTD (Basel, Switzerland).
Generation of dendritic cells and macrophages from peripheral blood (PB).
Peripheral blood mononuclear cells (PBMC) from healthy donors were isolated from freshly drawn PB by density centrifugation on Lymphoprep (Nycomed, Torshov, Norway). Subsequently, PBMC were centrifuged on a Percoll (Pharmacia, Uppsala, Sweden) gradient, consisting of three density layers (1.076, 1.059 and 1.045 g/mL). The light density fraction, containing predominantly monocytes, was seeded in 24 well-culture plates (Costar, Cambridge, MA) at a density of 0.5 × 106 cells/mL. After a 1-hour incubation at 37°C, nonadherent cells were removed and adherent cells were cultured in Iscove's modified Dulbecco's medium (IMDM; Life Technologies Ltd, Paisley, UK) and 10% fetal calf serum (FCS; Hyclone, Logan, UT), supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF ) (500 U/mL) to obtain macrophages (M ) or supplemented with GM-CSF and IL-4 (250 U/mL) to obtain DC.13,14 Every 2 days the media including the supplements were refreshed. After 6 days of culture, DC and M were procured and extensively washed before use.
Isolation of CD4+CD45RA+ naive and CD4+CD45R0+ memory T cells.
To obtain CD4+ T cells, peripheral blood lymphocytes (PBL) were procured from the lower interface of the Percoll gradient and were incubated with anti-CD4 coated dynabeads (Dynal AS, Oslo, Norway), followed by treatment with Detachabeads (Dynal AS), according to the manufacturer's instructions. Subsequently, CD4+ T cells were incubated at 4°C in petri dishes either coated with UCHL-1 (anti-CD45RO) or 2H4 (anti-CD45RA). After 2 hours, nonbound naive or memory T cells, respectively, were removed by gentle pipetting. This method yielded highly purified (>98%) CD4+CD45RA+ or CD4+CD45R0+ T cells as determined by FACS analysis (data not shown).
Stimulation of DC.
DC (40 × 103/well) were stimulated in 96-well flat-bottom culture plates (Costar) in IMDM containing 10% FCS in a final volume of 200 µL. The following stimuli were used: fixed Staphylococcus aureus Cowan strain I (SAC; 75 µg/mL; Calbiochem, San Diego, CA), lipopolysaccharide (LPS; 0.1 µg/mL; Difco, Detroit, MI), and soluble rCD40L containing a modified leucine zipper sequence17 (1 µg/mL; kindly provided by Immunex Research and Development Corp, Seattle, WA). This concentration of rCD40L was optimal for upregulation of adhesion molecules and IL-6 production by freshly isolated monocytes (data not shown). Furthermore, DC were incubated with 1 × 105 naive or memory Th cells, in the absence or presence of the superantigen staphylococcal enterotoxin A (SEA; 1 ng/mL; Serva, Heidelberg, Germany). All modes of stimulation were performed in the absence or presence of IFN- (1,000 U/mL). Supernatants were procured after 24 hours and IL-12 p70 levels were analyzed. Furthermore, supernatants of SAC-activated DC were used to study the effects of DC-derived soluble factors on the development of naive Th cells.
Mixed leukocyte reaction.
All T-cell cultures were performed in IMDM supplemented with 10% FCS, human transferrin (Behring-Werke, Marburg, Germany; 35 µg/mL) and human insulin (Novo Nordish A/S, Bagsvaerd, Denmark; 0.175 IU/mL). For mixed leucocyte reaction experiments, allogenic naive Th cells (6 × 104/well) were cocultured with different numbers of 3,000 rad irradiated DC, M, or freshly isolated monocytes in 96-well flat-bottom culture plates in a total volume of 200 µL. Proliferation was measured after 5 to 6 days by [3H]TdR incorporation, [3H]TdR being present the last 16 hours of culture (13 kBq/well; Radiochemical Center, Amersham, UK).
DC-dependent maturation of naive Th cells.
Because the precursor frequency of conventional Ag-specific Th cells is low in the naive Th cell population, naive Th cells (2 × 104/200 µL) were primed with the superantigen SEA, presented by irradiated (3,000 rad) autologous DC (4 × 104/200 µL). This resulted in a strong proliferative response, whereas in the absence of either DC or SEA no activation of T cells could be observed (data not shown). Both SAC-activated and nonactivated DC were used for priming, in the absence or presence of neutralizing polyclonal IL-12 antibodies (5 µg/mL). SAC activation of DC did not affect the proliferative response of the naive Th cells (data not shown). After 6 to 7 days rIL-2 (10 U/mL) was added and Th cells were further expanded for another 6 to 7 days. Within the culture period of 14 days, Th cells acquired the CD45RO memory phenotype, and the number of Th cells primed by DC under all different experimental conditions increased 200- to 500-fold (data not shown). Resting memory Th cells were procured, washed, and restimulated with immobilized CD3 MoAb and soluble CD28 MoAb. Supernatants were procured after 24 hours and levels of IFN- and IL-4 were analyzed.
DC-independent maturation of naive Th cells.
To study the functional maturation of naive Th cells in the absence of DC we used a culture system as described previously.18 Naive Th cells (2 × 104/200 µL) were stimulated with immobilized CD3 MoAb and soluble CD28 MoAb in the presence of rIL-2 (10 U/mL). These conditions resulted in optimal proliferation of the naive Th cells and resulted in the onset of production of both IL-4 and IFN-.18 Control experiments indicated that addition of SAC alone did not affect the cytokine profile of the maturing naive Th cells (data not shown). DC supernatants were added (final dilution 1:2), either or not in the presence of neutralizing anti-IL-12 (5 µg/mL). After 12 to 14 days of culturing, resting cells were procured, washed, and restimulated as described above.
Cytokine measurements.
Measurements of IFN- and IL-4 levels in the T-cell supernatants and IL-12 p70 in the DC supernatants were performed by specific solid-phase sandwich enzyme-linked immunosorbent assay (ELISA), as described previously.19-21 The limits of detection of these ELISAs are: IFN-: 100 pg/mL, IL-4: 50 pg/mL, IL-12 p70: 3 pg/mL.
| |
RESULTS |
Generation of DC from PB precursors.
The unique cell surface phenotype and the T-cell stimulatory capacity of the in vitro cultured DC were determined using in vitro cultured macrophages (M) or freshly isolated monocytes as control cells. DC expressed high levels CD1a but not CD14, whereas M expressed CD14 but not CD1a (Fig 1). Both APC types expressed HLA-DR, CD40, CD80, and CD86. However, DC expressed considerably higher levels of these surface molecules. The capacity of DC to stimulate naive T cells was determined by coculturing increasing numbers of DC, M, or monocytes with allogenic naive (CD45RA+CD45RO-) CD4+ T cells. These mixed leucocyte reactions demonstrated that DC were more potent stimulators of naive Th cells than M or monocytes (Fig 2). Only DC were capable of inducing proliferation by alloreactive naive Th cells at low cell numbers (150 cells/well) and, additionally, they induced the highest proliferative response at high cell numbers. Freshly isolated monocytes were even less efficient stimulator cells than M; only at the highest cell number tested (40 × 103 cells/well) a low proliferative T-cell response could be observed. Regarding the surface phenotype and potent capacity to stimulate naive Th cells, the in vitro cultured DC that we have used here resemble the previously described in vivo and in vitro DC types.14,15,22,23
View larger version (20K):
[in this window]
[in a new window]
| Fig 1.
Surface phenotype of DC and M. DC and M were generated by culturing PB monocytes for 6 days in the presence of GM-CSF with or without IL-4, respectively. Subsequently, the expression of several surface molecules was determined by FACS analysis; DC black histograms; M white histograms. Results are representative of eight independent experiments.
|
|
View larger version (16K):
[in this window]
[in a new window]
| Fig 2.
DC are more efficient stimulators of naive Th cells than M or freshly isolated monocytes. Different number of stimulator cells (stim.) all obtained from the same donor were cocultured with allogenic naive Th cells. The proliferative response was determined at day 6. The results are presented as mean counts per minute ± standard error of the mean (SEM) of triplicate cultures. Results are representative of three independent experiments.
|
|
Production of IL-12 by DC in response to different stimuli.
Next, the production of IL-12 p70 by DC on different modes of stimulation was determined (Fig 3). Stimulation of DC with SAC or LPS, which are potent inducers of IL-12 production in PBMC,24 resulted in the production of substantial amounts of IL-12. Recently, it was shown that CD40 ligand (CD40L), expressed on activated T cells, can induce IL-12 production in monocytes via interaction with CD40.25 However, despite the expression of high levels of CD40 (Fig 1), DC did not produce IL-12 on ligation of CD40 with soluble rCD40L (Fig 3).
View larger version (29K):
[in this window]
[in a new window]
| Fig 3.
Production of IL-12 p70 by DC. DC were stimulated with SAC, LPS, or soluble rCD40L in the absence or presence of IFN-. Supernatants were procured after 24 hours and levels of IL-12 p70 were analyzed. Results are presented as mean production ± SEM of four independent experiments.
|
|
As much as IFN- is a potent enhancer of IL-12 production by human monocytes,21,26,27 and IL-12 production by murine macrophages depends on the presence of IFN-,28 we also determined the IL-12 levels of DC that were stimulated in the presence of IFN- (Fig 3). IFN-, which by itself did not induce IL-12 production, strongly upregulated the production of IL-12 in response to either SAC or LPS. Notably, in the presence of IFN-, rCD40L also induced the production of large quantities of IL-12. In general, the IL-12 levels of the DC populations were comparable to, or even higher than, those of M. For instance, in response to SAC/IFN-, DC produced 870 ± 67 pg/mL IL-12 (n = 4), whereas M produced 365 ± 188 pg/mL IL-12 (n = 4), and in response to LPS/IFN-, DC produced 447 ± 25 pg/mL IL-12 (n = 4) and M produced 501 ± 86 pg/mL IL-12 (n = 4).
Summarizing, DC produce substantial levels of IL-12 in response to bacteria (SAC) or bacterial compounds (LPS), and these levels can be strongly upregulated by IFN-. In contrast, the induction of IL-12 via CD40-CD40L interaction in DC requires IFN- as an obligatory, complementary signal.
Naive Th cells require exogenous IFN- to induce IL-12 production in DC.
In a next series of experiments, we examined whether the interaction between DC and naive or memory Th cells resulted in the production of IL-12. Both naive and memory Th cells express CD40L rapidly on activation,29 but the production of IFN- by naive Th cells is relatively delayed, as compared to memory Th cells.18,30,31 Since the induction of IL-12 through CD40 ligation requires the complementary action of IFN-, we anticipated that activated memory, but not activated naive Th cells would be able to induce IL-12 production. To test this hypothesis, DC were incubated with either naive or memory Th cells, in the absence or presence of SEA and/or exogenous IFN-. Figure 4 clearly shows that the induction of IL-12 p70 production in DC required both the activation of naive Th cells with superantigen and the presence of exogenous IFN-. Activated memory cells, on the other hand, were capable of inducing the production of IL-12 p70 in DC in the absence of exogenous IFN-, probably because the endogenous IFN- levels in these cultures were sufficient to allow for the induction of IL-12 production. Interestingly, even in the absence of exogenous IFN-, activated naive Th cells induced the production of the p40 subunit of IL-12 by DC (data not shown). Levels of IL-12 p40 were similar to the p40 levels induced by activated memory Th cells or SAC (± 3 ng/mL). Similar results were obtained when the naive and memory Th cells were preactivated for 16 hours with stimulatory MoAbs directed against CD3 and CD28 (data not shown). Furthermore, control experiments showed that SEA and/or IFN- without T cells did not induce the production of IL-12 p70 (data not shown). These results demonstrate that in contrast to activated memory Th cells, activated naive Th cells are poor inducers of IL-12 production by DC.
View larger version (20K):
[in this window]
[in a new window]
| Fig 4.
Naive Th cells require exogenous IFN- to induce IL-12 production in DC. Naive or memory Th cells were incubated with autologous DC, in the absence or presence of SEA to activate the Th cells and rIFN-. Supernatants were procured after 24 hours and levels of IL-12 p70 were analyzed. Result are presented as mean production IL-12 p70 ± SEM of triplicate cultures. Data are representative of three independent experiments.
|
|
Induction of Th1 development by DC requires an exogenous IL-12-inducing factor.
Subsequently, the role of DC in skewing the cytokine profile of naive Th cells was studied, focusing on the role of DC-derived IL-12. For this purpose, naive Th cells were activated by SEA presented by autologous DC that were or were not activated with SAC. Endogenous IL-12 production was neutralized with anti-IL-12. Similar high proliferative responses of the naive Th cells were observed under all conditions (data not shown). After addition of rIL-2 at day 6 to 7, Th cells were cultured for another 6 to 7 days until they had reached a resting state, and their cytokine profiles were analyzed after restimulation with CD3 and CD28 MoAbs.
As shown in Fig 5, priming of naive Th cells with nonactivated DC promoted the development of memory Th0 cells producing comparable amounts of the type 1 cytokine IFN- and the type 2 cytokine IL-4. Neutralization of endogenous IL-12 decreased IFN- levels only to a limited extent, indicating that under these conditions IL-12 does not play a major skewing role, as could be expected from the observation that naive Th cells are poor inducers of IL-12 production in DC (Fig 4).
View larger version (12K):
[in this window]
[in a new window]
| Fig 5.
SAC-activated DC direct Th1 development from naive Th cells through the release of IL-12. Naive Th cells were activated by SEA presented by autologous DC. DC were or were not activated with SAC and endogenous IL-12 production was or was not neutralized with anti-IL-12 ( IL-12). Th cells were cultured for 14 days, the last 7 days in the presence of rIL-2 and restimulated with CD3 and CD28 MoAb. Supernatants were procured after 24 hours and levels of IL-4 and IFN- were analyzed. Results are shown as duplicate points representing two independent primary cultures treated under identical conditions in the same experiment. Data are representative of three independent experiments.
|
|
In contrast, priming of the naive Th cells with SAC-activated DC always resulted in the development of Th1-like cells, producing high quantities of IFN- and low quantities of IL-4. In these cultures Th1 development was clearly mediated by DC-derived IL-12, because addition of neutralizing IL-12 antibodies completely abolished the increased IFN- production and, additionally, resulted in enhanced IL-4 production. Irrelevant isotype-matched control antibodies did not exert these effects (data not shown).
Next, we determined whether the SAC-induced Th1 development was indeed solely due to the SAC-induced production of IL-12 or that membrane molecules expressed by DC played a role in this respect. For this purpose, an accessory cell-independent T-cell maturation model was applied.18 In this model naive Th cells are activated by a combination of CD3 and CD28 MoAbs in the presence of rIL-2. The effect of DC-derived IL-12 was established by adding supernatants of 24 hours SAC-activated DC with or without neutralizing IL-12 antibodies. The production of IFN- and IL-4 by these Th cell cultures on restimulation with CD3 and CD28 MoAb were determined and compared to Th cell cultures that matured in the presence of rIL-12 (200 U/mL). Figure 6 shows that Th cells cultured in the presence of either rIL-12 or supernatants of SAC-activated DC produced higher levels of IFN- and, simultaneously, lower levels of IL-4 than control cultures, and that neutralizing anti-IL-12 antibodies completely abolished the regulatory effects of DC-supernatants on the onset of cytokine production. Control experiments indicated that irrelevant isotype-matched antibodies and supernatants of unactivated DC had no effect (data not shown).
View larger version (27K):
[in this window]
[in a new window]
| Fig 6.
IL-12 is the major Th1-skewing factor in supernatants of SAC-activated DC. Naive Th cells were stimulated with CD3 MoAb and CD28 MoAb in the presence of rIL-2. rIL-12 (200 U/mL) or supernatants of 24-hour activated DC (DC-sup; final dilution 1:2) were added, the latter in the absence or presence of neutralizing anti-IL-12 (IL-12). Th cells were cultured for 14 days and restimulated with CD3 and CD28 MoAb. Supernatants were procured after 24 hours and levels of IFN- and IL-4 were analyzed. Results are expressed as the percentage (mean ± SEM of three independent experiments) of the cytokine production of Th cells that were cultured in the absence of rIL-12, DC-sup, and IL-12.
|
|
Together, these data show that DC induce the development of naive Th cell populations into Th0 cell populations, producing both IFN- and IL-4, because the interaction between DC and naive Th cells does not facilitate the induction of IL-12 production. Therefore, the induction of Th1 development through DC-derived IL-12 requires the action of an exogenous IL-12-inducing factor.
| |
DISCUSSION |
The present study shows that human DC are potent producers of IL-12. The induction of the development of Th1 cells from naive Th cells through DC-derived IL-12, however, requires the action of exogenous IL-12-inducing factors, because the interaction between DC and naive Th cells does not facilitate the induction of IL-12 production in DC. In the absence of IL-12-inducing factors, DC efficiently promote the production of both IL-4 and IFN- in maturing naive Th cell populations.
The DC populations used in this study were clearly superior to M with respect to the expression of MHC class II and costimulatory molecules, and the capacity to stimulate naive Th cells. Like M and monocytes, these DC produce IL-12 in response to well-known IL-12-inducers such as SAC and LPS and, additionally, their IL-12 levels can be strongly upregulated by IFN-.21,26,27 Although the amounts of IL-12 p70 induced by SAC-activation alone appeared to be relatively low, our functional data show that these low amounts are sufficient to induce Th1 development. In fact, supernatants of SAC-activated DC (containing ± 30 pg/mL IL-12) were equally effective in this respect as an excess of rIL-12.
The finding that IL-12 production by in vitro cultured human DC can be induced by stimuli such as SAC or LPS are in line with the results from other groups6,32 but appear to be in contrast with another, recently published study.8 However, these different results may be explained by the relatively low sensitivity of the IL-12 p70 ELISA (50 pg/mL) applied in the latter study.
Another IL-12-inducing pathway is the interaction between CD40L expressed by activated T cells and CD40 expressed by APC.25,33 Here we have shown that IL-12 production by DC after ligation of CD40 requires the complementary action of IFN-. This action of IFN- cannot merely be attributed to its upregulatory effect on CD40 expression, since DC already express high levels of CD40 in the absence of IFN-. Another, more likely, explanation may be that the expression of the IL-12 p35 and p40 subunits is differentially regulated on activation via CD40 or IFN-. CD40-CD40L interaction stimulates the mRNA accumulation of the p40 subunit, but not of the p35 subunit (33 and our own unpublished observation, June 1996), whereas IFN- directly induces transcription of the p35 gene.34
Apparently in contrast to our results, Cella et al8 reported that ligation of CD40 on DC is sufficient for the induction of high IL-12 levels. However, since they used CD40L-transfected J588L cells instead of rCD40L, it cannot be excluded that these cells release soluble factor(s) that, like IFN-, can complement the action of CD40 ligation by directly inducing the transcription of the p35 gene and/or can strongly enhance IL-12 production. The fact that in their experiments exogenous IFN- exerted only marginal upregulatory effects on the production of IL-12 actually supports this possibility.
The observation that CD40-CD40L interaction by itself is not sufficient for the induction of IL-12 production, explains our finding that DC-induced Th1 development from naive Th cells does not occur via a default differentiation pathway, but specifically requires an exogenous IL-12-inducing factor. Although CD40L on naive Th cells is expressed within 6 hours of activation,29 secretion of IFN- by activated naive Th cells is only detectable after 3 to 4 days.18,30,31 Thus, under these conditions the IFN--requirement of DC to produce IL-12 on ligation of CD40 is not fulfilled. Indeed, here we have shown that in contrast to activated memory Th cells, naive Th cells are poor inducers of IL-12 production in DC, unless exogenous IFN- is present. Consequently, DC will not direct the development of naive Th cells toward the Th1 phenotype. Therefore,it may be anticipated that in the presence of exogenous IFN- during activation of naive Th cells by DC, the development of Th1 cells is facilitated through the induction of IL-12 production. Indeed, addition of rIFN- during the superantigen-priming of naive Th cells by DC resulted in the development of Th1 cells, an effect that was clearly dependent of DC, since no skewing effect of rIFN- was observed during the DC-independent maturation of naive Th cells (data not shown). Thus, it may be argued that, in addition to potent IL-12-inducers such as SAC, microenvironmental IFN- instructs DC to skew naive Th cells toward the Th1 phenotype.
Murine in vitro studies have indicated that DC preferentially promote the development of Th1 cells.5,6 In the study of Macatonia et al,5 however, it was shown that only in the absence of endogenous IL-4 during the primary activation of Th cells, Th1 responses could be driven by DC through the production of IL-12. In our culture system, on the other hand, endogenous IL-4 did not appear to play a major role in this respect, since IL-4 was never detected in primary cultures, nor was the skewing potential of DC affected by the addition of neutralizing anti-IL-4 (data not shown). The other mouse model study6 showed that polarized Th1 cytokine profiles were obtained after repetitive cycles of stimulation with DC. Under these conditions, Th1 development probably follows from CD40L-induced IL-12 production facilitated by the production of IFN- by matured Th cells, which occurs relatively rapidly after stimulation.
The observation that in the absence of IL-12-inducers human DC induce both IL-4 and IFN- production in maturing Th cells is in keeping with data from several murine in vivo studies. Ronchese et al35 showed that DC pulsed with protein Ag efficiently prime IL-4- and IFN--producing Ag-specific T cells. Furthermore, evaluation of specific immune responses after epicutaneously application of Ag revealed that IL-12-inducing chemical haptens promoted a Th1 response,36 whereas protein Ag resulted in a Th2/Th0 or even a Th2 response, depending on the time course of sensitization.37
The capacity of DC to prime the production of IL-4 may be partly attributed to their high surface expression of CD80/CD86 and/or CD40. It was reported by various groups that ligation of the counterparts of these molecules, ie, CD28 and CD40L, respectively, promotes the induction of IL-4 production in naive Th cells.18,38-41 However, these IL-4-inducing pathways are clearly dominated by the action of IL-12, which strongly inhibits the onset of IL-4 production in naive Th cells.
In conclusion, the present findings support the concept that the nature of the Th cell response is not fixed by the intrinsic properties of DC, but is highly influenced by the biological activities of the Ag and/or microenvironmental factors. Thus, by inducing IL-12 production in DC, bacteria, bacterial compounds, or exogenous IFN-, eg, derived from activated bystander memory T cells or NK cells, will promote the development of Th1 responses. Conversely, Th2/Th0 responses will be facilitated by microenvironmental factors that inhibit the production of IL-12 by DC, such as IL-1042 and prostaglandin E2.43 The impact of these and other factors on the cytokine profile of DC and the consequences for the development of naive Th cells are currently under investigation.
| |
FOOTNOTES |
Submitted October 28, 1996;
accepted April 22, 1997.
Supported by a grant from the Netherlands Organization for Scientific Research (The Hague) (900-505-251 to C.M.U.H.).
Address reprint requests to Catharien M.U. Hilkens, PhD, Academic Medical Center, University of Amsterdam, Department of Cell Biology & Histology, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hearly marked
``advertisment'' in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank J. Schuitemaker for excellent technical assistance.
| |
REFERENCES |
1.
Steinman RM:
The dendritic cell system and its role in immunogenicity.
Annu Rev Immunol
9:271,
1991[Medline]
[Order article via Infotrieve]
2.
Trinchieri G:
Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.
Annu Rev Immunol
13:251,
1995[Medline]
[Order article via Infotrieve]
3.
Hsieh CS,
Macatonia SE,
Tripp CS,
Wolf SF,
O'Garra A,
Murphy KM:
Development of Th1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages.
Science
260:547,
1993[Abstract/Free Full Text]
4.
Manetti R,
Parronchi P,
Giudzi MG,
Piccinni MP,
Maggi E,
Trinchieri G,
Romagnani S:
Natural Killer Stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing cells.
J Exp Med
177:1199,
1993[Abstract/Free Full Text]
5.
Macatonia SE,
Hosken NA,
Litton M,
Vieira P,
Hsieh CY,
Culpepper JA,
Wysocka M,
Trinchieri G,
Murphy KM,
O'Garra A:
Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells.
J Immunol
154:5071,
1995[Abstract]
6.
Heufler C,
Koch F,
Stanzl U,
Topar G,
Wysocka M,
Trinchieri G,
Enk A,
Steinman RM,
Romani N,
Schuler G:
Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon- production by T helper 1 cells.
Eur J Immunol
26:659,
1996[Medline]
[Order article via Infotrieve]
7.
Kang K,
Kubin M,
Cooper KD,
Lessin SR,
Trinchieri G,
Rook AH:
IL-12 synthesis by human Langerhans cells.
J Immunol
156:1402,
1996[Abstract]
8.
Cella M,
Scheidegger D,
Palmer-Lehmann K,
Lane P,
Lanzavecchia A,
Alber G:
Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation.
J Exp Med
184:747,
1996[Abstract/Free Full Text]
9. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley M: 1989 Reciprocal expression of interferon or interleukin 4 during the resolution or progression of murine leishmaniasis J Exp Med 169:59, 1989
10.
Salgame P,
Abrams JS,
Clayberger C,
Goldstein H,
Convit J,
Modlin RL,
Bloom BR:
Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones.
Science
254:279,
1991[Abstract/Free Full Text]
11.
Gazinelli RT,
Hieny S,
Wynn TA,
Wolf S,
Sher A:
Interleukin 12 is required for the T-lymphocyte-independent induction of IFN- by an intracellular parasite and induces resistance in T-cell-deficient hosts.
Proc Natl Acad Sci USA
90:6115,
1993[Abstract/Free Full Text]
12. Finkelman FD, Pearce EJ, Urban JF Jr, Sher A: Regulation and biological function of helminth-induced cytokine responses. Immunol Today 12:A62, 1991
13.
Liblau RS,
Singer SM,
McDevitt HO:
Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.
Immunol Today
16:34,
1995[Medline]
[Order article via Infotrieve]
14.
Sallusto F,
Lanzavecchia A:
Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor .
J Exp Med
179:1109,
1994[Abstract/Free Full Text]
15.
Romani N,
Gruner S,
Brang D,
Kämpgen E,
Lenz A,
Trockenbacher B,
Konwalinka TG,
Fritsch PO,
Steinman RM,
Schuler G:
Proliferating dendritic cell progenitors in human blood.
J Exp Med
180:83,
1994[Abstract/Free Full Text]
16.
de Boer M,
Parren P,
Dove J,
Ossendorp FA,
van der Horstand G,
Reeder J:
Functional characterization of a novel anti-B7 monoclonal antibody.
Eur J Immunol
22:3071,
1992[Medline]
[Order article via Infotrieve]
17.
Fanslow WC,
Srinivasan S,
Paxton R,
Gibson MG,
Spriggs MK,
Armitage RJ:
structural characteristics of CD40 ligand that determine biological function.
Semin Immunol
6:267,
1994[Medline]
[Order article via Infotrieve]
18.
Kalinski P,
Hilkens CMU,
Wierenga EA,
van der Pouw Kraan TCTM,
van Lier RAW,
Bos JD,
Kapsenberg ML,
Snijdewint FGM:
Functional maturation of human naive T helper cells in the absence of accessory cells.
J Immunol
154:3753,
1995[Abstract]
19.
Van der Meide PH,
Dubbeld M,
Schellekens H:
Monoclonal antibodies to human interferon and their use in a sensitive solid-phase ELISA.
J Immunol Methods
79:293,
1985[Medline]
[Order article via Infotrieve]
20.
Van der Pouw Kraan T,
Rensink I,
Aarden L:
Characterisation of monoclonal antibodies to human IL-4: Application in an IL-4 ELISA and differential inhibition of IL-4 bioactivity on B cells and T cells.
Eur Cytokine Netw
4:343,
1993[Medline]
[Order article via Infotrieve]
21.
Snijders A,
Hilkens CMU,
van der Pouw Kraan TCTM,
Engel M,
Aarden LA,
Kapsenberg ML:
Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit.
J Immunol
156:1207,
1996[Abstract]
22.
Thomas R,
Lipsky PE:
Human peripheral blood dendritic cell subsets.
J Immunol
153:4016,
1994[Abstract]
23.
Croft M,
Duncan DD,
Swain SL:
Response of naive antigen-specific CD4+ T cells in vitro: Characteristics and antigen-presenting cell requirements.
J Exp Med
176:1431,
1992[Abstract/Free Full Text]
24.
D'Andrea A,
Rengaraju M,
Valiante NM,
Chehimi J,
Kubin M,
Aste M,
Chan SH,
Kobayashi M,
Young D,
Nickbarg E,
Chizzonite R,
Wolf SF,
Trinchieri G:
Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells.
J Exp Med
176:1387,
1992[Abstract/Free Full Text]
25.
Shu U,
Kiniwa M,
Wu CY,
Maliszewski C,
Vezzio N,
Hakimi J,
Gately M,
Delespesse G:
Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction.
Eur J Immunol
25:1125,
1995[Medline]
[Order article via Infotrieve]
26.
Kubin M,
Chowand JM,
Trinchieri G:
Differential regulation of interleukin-12 (IL-12), tumor necrosis factor and IL-1 production in human myeloid leukemia cell lines and peripheral blood mononuclear cells.
Blood
83:1847,
1994[Abstract/Free Full Text]
27.
Hayes MP,
Wang J,
Norcross M:
Regulation of interleukin-12 expression in human monocytes: selective priming by interferon- of lipopolysaccharide-inducible p35 and p40 genes.
Blood
86:646,
1995[Abstract/Free Full Text]
28.
Flesch IEA,
Hess JH,
Huang S,
Aguet M,
Rothe J,
Bluethman H,
Kaufmann SHE:
Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon and tumor necrosis factor .
J Exp Med
181:1615,
1995[Abstract/Free Full Text]
29.
Patel HR,
Oshiba A,
Jeppson JD,
Gelfand EW:
Differential expression of CD40 ligand on T cell subsets.
J Immunol
156:1781,
1996[Abstract]
30.
Dohlsten M,
Hedlund G,
Sjögren H,
Carlsson R:
Two subsets of human CD4+ T helper cells differing in kinetics and capacities to produce interleukin 2 and interferon- can be defined by the Leu-18 and UCHL1 monoclonal antibodies.
Eur J Immunol
18:1173,
1988[Medline]
[Order article via Infotrieve]
31.
Butch AW,
Pesando J,
Levine AD,
Mckearn JP,
Nahm MH:
Cytokine production by T helper subpopulations during prolonged in vitro stimulation.
Immunol Lett
27:85,
1991[Medline]
[Order article via Infotrieve]
32.
Verhasselt V,
Buelens C,
Willems F,
De Groote D,
Haeffner-Cavaillon N,
Goldman M:
Bacterial LPS stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cells: Evidence for a soluble CD14-dependent pathway.
J Immunol
158:2919,
1997[Abstract]
33.
Kato T,
Hakamada R,
Yamane H,
Nariuchi H:
Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40-CD40 ligand interaction.
J Immunol
156:3932,
1996[Abstract]
34.
Ma X,
Chow JM,
Gri G,
Carra G,
Gerosa F,
Wolf SF,
Dzialo R,
Trinchieri G:
The interleukin 12 p40 gene promotor is primed by interferon in monocytic cells.
J Exp Med
183:147,
1996[Abstract/Free Full Text]
35.
Ronchese F,
Hausmann B,
Le Gros GL:
Interferon-- and interleukin-4- producing Tn cells can be primed on dendritic cells in vivo and do not require the presence of B cells.
Eur J Immunol
24:1148,
1994[Medline]
[Order article via Infotrieve]
36.
Riemann H,
Schwartz A,
Grabbe S,
Aragane Y,
Luger TA,
Wysocka M,
Kubin M,
Trinchieri G,
Schwarz T:
Neutralization of IL-12 in vivo prevents induction of contact hypersensitivity and induces hapten-specific tolerance.
J Immunol
156:1799,
1996[Abstract]
37.
Wang LF,
Lin JY,
Hsiehand KH,
Lin RH:
Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice.
J Immunol
156:4079,
1996[Abstract]
38.
Freeman GJ,
Boussiotis VA,
Anumanthan A,
Bernstein GM,
Ke XY,
Rennert PD,
Gray GS,
Gribben JG,
Nadler LM:
B7-1 and B7-2 do not deliver identical co-stimulatory signals since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4.
Immunity
2:523,
1995[Medline]
[Order article via Infotrieve]
39.
King CL,
Stupi RJ,
Graighead N,
June CH,
Thyphronitis G:
CD28 activation promotes Th2 subset differentiation by human CD4+ cells.
Eur J Immunol
25:587,
1995[Medline]
[Order article via Infotrieve]
40.
Webb LMC,
Feldmann M:
Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells.
Blood
86:3479,
1995[Abstract/Free Full Text]
41.
Blotta MH,
Marshall JD,
DeKruyff RH,
Umetsu DT:
Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis.
J Immunol
156:3133,
1996[Abstract]
42.
D'Andrea A,
Aste-Amezaga M,
Valiante NM,
Ma X,
Kubin M,
Trinchieri G:
Interleukin 10 (IL-10) inhibits human lymphocyte interferon -production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells.
J Exp Med
178:1041,
1993[Abstract/Free Full Text]
43.
Van der Pouw Kraan TCTM,
Boeije LC,
Smeenk RJT,
Wijdenes J,
Aarden LA:
Prostaglandin E2 is a potent inhibitor of human interleukin 12 production.
J Exp Med
181:775,
1995[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. R. Hensler, G. Rappocciolo, C. R. Rinaldo, and F. J. Jenkins
Cytokine production by human herpesvirus 8-infected dendritic cells
J. Gen. Virol.,
January 1, 2009;
90(1):
79 - 83.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Pietrella, P. Lupo, A. Rachini, S. Sandini, A. Ciervo, S. Perito, F. Bistoni, and A. Vecchiarelli
A Candida albicans Mannoprotein Deprived of Its Mannan Moiety Is Efficiently Taken Up and Processed by Human Dendritic Cells and Induces T-Cell Activation without Stimulating Proinflammatory Cytokine Production
Infect. Immun.,
September 1, 2008;
76(9):
4359 - 4367.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Marcenaro, B. Ferranti, M. Falco, L. Moretta, and A. Moretta
Human NK cells directly recognize Mycobacterium bovis via TLR2 and acquire the ability to kill monocyte-derived DC
Int. Immunol.,
September 1, 2008;
20(9):
1155 - 1167.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Mukherjee and V. S. Chauhan
Plasmodium falciparum-free merozoites and infected RBCs distinctly affect soluble CD40 ligand-mediated maturation of immature monocyte-derived dendritic cells
J. Leukoc. Biol.,
July 1, 2008;
84(1):
244 - 254.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Lehner, A. Stilper, P. Morhart, and W. Holter
Plasticity of dendritic cell function in response to prostaglandin E2 (PGE2) and interferon-{gamma} (IFN-{gamma})
J. Leukoc. Biol.,
April 1, 2008;
83(4):
883 - 893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. C. Connolly, T. L. Whiteside, C. Wilson, V. Kondragunta, C. R. Rinaldo, and S. A. Riddler
Therapeutic Immunization with Human Immunodeficiency Virus Type 1 (HIV-1) Peptide-Loaded Dendritic Cells Is Safe and Induces Immunogenicity in HIV-1-Infected Individuals
Clin. Vaccine Immunol.,
February 1, 2008;
15(2):
284 - 292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Fan, X.-L. Huang, P. Kalinski, S. Young, and C. R. Rinaldo Jr.
Dendritic Cell Function during Chronic Hepatitis C Virus and Human Immunodeficiency Virus Type 1 Infection
Clin. Vaccine Immunol.,
September 1, 2007;
14(9):
1127 - 1137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Haniffa, X.-N. Wang, U. Holtick, M. Rae, J. D. Isaacs, A. M. Dickinson, C. M. U. Hilkens, and M. P. Collin
Adult Human Fibroblasts Are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells
J. Immunol.,
August 1, 2007;
179(3):
1595 - 1604.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Takenaka, E. Safroneeva, Z. Xing, and J. Gauldie
Dendritic Cells Derived from Murine Colonic Mucosa Have Unique Functional and Phenotypic Characteristics
J. Immunol.,
June 15, 2007;
178(12):
7984 - 7993.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. Flores, K. A. Diggs, L. M. Tait, and P. A. Morel
IFN-{gamma} Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells
J. Immunol.,
January 1, 2007;
178(1):
211 - 218.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kitawaki, N. Kadowaki, N. Sugimoto, N. Kambe, T. Hori, Y. Miyachi, T. Nakahata, and T. Uchiyama
IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells
Int. Immunol.,
December 1, 2006;
18(12):
1789 - 1799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Bellone, A. Carbone, C. Smirne, T. Scirelli, A. Buffolino, A. Novarino, A. Stacchini, O. Bertetto, G. Palestro, C. Sorio, et al.
Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells.
J. Immunol.,
September 1, 2006;
177(5):
3448 - 3460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Macagno, M. Molteni, A. Rinaldi, F. Bertoni, A. Lanzavecchia, C. Rossetti, and F. Sallusto
A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression
J. Exp. Med.,
June 12, 2006;
203(6):
1481 - 1492.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Cao, P. Tan, C. H. Lee, H. Zhang, and J. Lu
A transforming growth factor-beta-induced protein stimulates endocytosis and is up-regulated in immature dendritic cells
Blood,
April 1, 2006;
107(7):
2777 - 2785.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Cenci, E. Pericolini, A. Mencacci, S. Conti, W. Magliani, F. Bistoni, L. Polonelli, and A. Vecchiarelli
Modulation of phenotype and function of dendritic cells by a therapeutic synthetic killer peptide
J. Leukoc. Biol.,
January 1, 2006;
79(1):
40 - 45.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Rubio, T. K. Means, R. Chakraverty, J. Shaffer, Y. Fudaba, M. Chittenden, A. D. Luster, and M. Sykes
Maturation of human monocyte-derived dendritic cells (MoDCs) in the presence of prostaglandin E2 optimizes CD4 and CD8 T cell-mediated responses to protein antigens: role of PGE2 in chemokine and cytokine expression by MoDCs
Int. Immunol.,
December 1, 2005;
17(12):
1561 - 1572.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Oki, C. Tomi, T. Yamamura, and S. Miyake
Preferential Th2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo
Int. Immunol.,
December 1, 2005;
17(12):
1619 - 1629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Mailliard, S. M. Alber, H. Shen, S. C. Watkins, J. M. Kirkwood, R. B. Herberman, and P. Kalinski
IL-18-induced CD83+CCR7+ NK helper cells
J. Exp. Med.,
October 3, 2005;
202(7):
941 - 953.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Renkl, J. Wussler, T. Ahrens, K. Thoma, S. Kon, T. Uede, S. F. Martin, J. C. Simon, and J. M. Weiss
Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype
Blood,
August 1, 2005;
106(3):
946 - 955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Cumberbatch, K. Clelland, R. J. Dearman, and I. Kimber
Impact of Cutaneous IL-10 on Resident Epidermal Langerhans' Cells and the Development of Polarized Immune Responses
J. Immunol.,
July 1, 2005;
175(1):
43 - 50.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tabata, N. Kadowaki, T. Kitawaki, T. Shimaoka, S. Yonehara, O. Yoshie, and T. Uchiyama
Distribution and kinetics of SR-PSOX/CXCL16 and CXCR6 expression on human dendritic cell subsets and CD4+ T cells
J. Leukoc. Biol.,
May 1, 2005;
77(5):
777 - 786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Chagnon, S. Tanguay, O. L. Ozdal, M. Guan, Z. Z. Ozen, J.-S. Ripeau, M. Chevrette, M. M. Elhilali, and L. A. Thompson-Snipes
Potentiation of a Dendritic Cell Vaccine for Murine Renal Cell Carcinoma by CpG Oligonucleotides
Clin. Cancer Res.,
February 1, 2005;
11(3):
1302 - 1311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tavakoli, W. Schwerin, A. Rohwer, S. Hoffmann, S. Weyer, R. Weth, H. Meisel, H. Diepolder, M. Geissler, P. R. Galle, et al.
Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection
J. Gen. Virol.,
October 1, 2004;
85(10):
2829 - 2836.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kikuchi, C. L. Hahn, S. Tanaka, S. E. Barbour, H. A. Schenkein, and J. G. Tew
Dendritic Cells Stimulated with Actinobacillus actinomycetemcomitans Elicit Rapid Gamma Interferon Responses by Natural Killer Cells
Infect. Immun.,
September 1, 2004;
72(9):
5089 - 5096.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Rivas-Carvalho, M. A. Meraz-Rios, L. Santos-Argumedo, S. Bajana, G. Soldevila, M. E. Moreno-Garcia, and C. Sanchez-Torres
CD16+ human monocyte-derived dendritic cells matured with different and unrelated stimuli promote similar allogeneic Th2 responses: regulation by pro- and anti-inflammatory cytokines
Int. Immunol.,
September 1, 2004;
16(9):
1251 - 1263.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Wassink, P. L. Vieira, H. H. Smits, G. A. Kingsbury, A. J. Coyle, M. L. Kapsenberg, and E. A. Wierenga
ICOS Expression by Activated Human Th Cells Is Enhanced by IL-12 and IL-23: Increased ICOS Expression Enhances the Effector Function of Both Th1 and Th2 Cells
J. Immunol.,
August 1, 2004;
173(3):
1779 - 1786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Matsushima, N. Yamada, H. Matsue, and S. Shimada
TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells
J. Immunol.,
July 1, 2004;
173(1):
531 - 541.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Rouas, P. Lewalle, F. El Ouriaghli, B. Nowak, H. Duvillier, and P. Martiat
Poly(I:C) used for human dendritic cell maturation preserves their ability to secondarily secrete bioactive IL-12
Int. Immunol.,
May 1, 2004;
16(5):
767 - 773.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. R. O'Donnell, B. G. Toelle, G. B. Marks, C. M. Hayden, I. A. Laing, J. K. Peat, J. Goldblatt, and P. N. Le Souef
Age-specific Relationship between CD14 and Atopy in a Cohort Assessed from Age 8 to 25 Years
Am. J. Respir. Crit. Care Med.,
March 1, 2004;
169(5):
615 - 622.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Athie-Morales, H. H. Smits, D. A. Cantrell, and C. M. U. Hilkens
Sustained IL-12 Signaling Is Required for Th1 Development
J. Immunol.,
January 1, 2004;
172(1):
61 - 69.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. P. Oliveira, G. M. A. C. Lima, M. T. Shio, P. J. M. Leenen, and I. A. Abrahamsohn
Immature macrophages derived from mouse bone marrow produce large amounts of IL-12p40 after LPS stimulation
J. Leukoc. Biol.,
November 1, 2003;
74(5):
857 - 867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Bedrosian, R. Mick, S. Xu, H. Nisenbaum, M. Faries, P. Zhang, P. A. Cohen, G. Koski, and B. J. Czerniecki
Intranodal Administration of Peptide-Pulsed Mature Dendritic Cell Vaccines Results in Superior CD8+ T-Cell Function in Melanoma Patients
J. Clin. Oncol.,
October 15, 2003;
21(20):
3826 - 3835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Miyazaki, H. Tsuda, M. Sakai, S. Hori, Y. Sasaki, T. Futatani, T. Miyawaki, and S. Saito
Predominance of Th2-promoting dendritic cells in early human pregnancy decidua
J. Leukoc. Biol.,
October 1, 2003;
74(4):
514 - 522.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. E. Smith, V. Patel, S. D. Seatter, M. R. Deehan, M. H. Brown, G. P. Brooke, H. S. Goodridge, C. J. Howard, K. P. Rigley, W. Harnett, et al.
A novel MyD-1 (SIRP-1{alpha}) signaling pathway that inhibits LPS-induced TNF{alpha} production by monocytes
Blood,
October 1, 2003;
102(7):
2532 - 2540.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. T. Semnani, A. Y. Liu, H. Sabzevari, J. Kubofcik, J. Zhou, J. K. Gilden, and T. B. Nutman
Brugia malayi Microfilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4+ T Cells
J. Immunol.,
August 15, 2003;
171(4):
1950 - 1960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. L. Vieira, H. C. Heystek, J. Wormmeester, E. A. Wierenga, and M. L. Kapsenberg
Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells
J. Immunol.,
May 1, 2003;
170(9):
4483 - 4488.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Jinushi, T. Takehara, T. Kanto, T. Tatsumi, V. Groh, T. Spies, T. Miyagi, T. Suzuki, Y. Sasaki, and N. Hayashi
Critical Role of MHC Class I-Related Chain A and B Expression on IFN-{alpha}-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection
J. Immunol.,
February 1, 2003;
170(3):
1249 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Leslie, M. S. Vincent, F. M. Spada, H. Das, M. Sugita, C. T. Morita, and M. B. Brenner
CD1-mediated {gamma}/{delta} T Cell Maturation of Dendritic Cells
J. Exp. Med.,
December 16, 2002;
196(12):
1575 - 1584.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. P. Boonacker, E. A. Wierenga, H. H. Smits, and C. J.F. Van Noorden
CD26/DPPIV Signal Transduction Function, but Not Proteolytic Activity, Is Directly Related to Its Expression Level on Human Th1 and Th2 Cell Lines as Detected with Living Cell Cytochemistry
J. Histochem. Cytochem.,
September 1, 2002;
50(9):
1169 - 1177.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. E. Lokshin, P. Kalinski, R. R. Sassi, R. B. Mailliard, J. Muller-Berghaus, W. J. Storkus, X. Peng, A. M. Marrangoni, R. P. Edwards, and E. Gorelik
Differential regulation of maturation and apoptosis of human monocyte-derived dendritic cells mediated by MHC class II
Int. Immunol.,
September 1, 2002;
14(9):
1027 - 1037.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. McDowell, M. Marovich, R. Lira, M. Braun, and D. Sacks
Leishmania Priming of Human Dendritic Cells for CD40 Ligand-Induced Interleukin-12p70 Secretion Is Strain and Species Dependent
Infect. Immun.,
August 1, 2002;
70(8):
3994 - 4001.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Mailliard, S. Egawa, Q. Cai, A. Kalinska, S. N. Bykovskaya, M. T. Lotze, M. L. Kapsenberg, W. J. Storkus, and P. Kalinski
Complementary Dendritic Cell-activating Function of CD8+ and CD4+ T Cells: Helper Role of CD8+ T Cells in the Development of T Helper Type 1 Responses
J. Exp. Med.,
February 19, 2002;
195(4):
473 - 483.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. F. Lipscomb and B. J. Masten
Dendritic Cells: Immune Regulators in Health and Disease
Physiol Rev,
January 1, 2002;
82(1):
97 - 130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. R. Christensen, H. Frokiar, and J. J. Pestka
Lactobacilli Differentially Modulate Expression of Cytokines and Maturation Surface Markers in Murine Dendritic Cells
J. Immunol.,
January 1, 2002;
168(1):
171 - 178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Caron, Y. Delneste, E. Roelandts, C. Duez, J.-Y. Bonnefoy, J. Pestel, and P. Jeannin
Histamine Polarizes Human Dendritic Cells into Th2 Cell-Promoting Effector Dendritic Cells
J. Immunol.,
October 1, 2001;
167(7):
3682 - 3686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. T. Semnani, H. Sabzevari, R. Iyer, and T. B. Nutman
Filarial Antigens Impair the Function of Human Dendritic Cells during Differentiation
Infect. Immun.,
September 1, 2001;
69(9):
5813 - 5822.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. E. Morelli, A. F. Zahorchak, A. T. Larregina, B. L. Colvin, A. J. Logar, T. Takayama, L. D. Falo, and A. W. Thomson
Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation
Blood,
September 1, 2001;
98(5):
1512 - 1523.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Wesa and A. Galy
IL-1{beta} induces dendritic cells to produce IL-12
Int. Immunol.,
August 1, 2001;
13(8):
1053 - 1061.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Santiago-Schwarz, P. Anand, S. Liu, and S. E. Carsons
Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses
J. Immunol.,
August 1, 2001;
167(3):
1758 - 1768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kalinski, P. L. Vieira, J. H. N. Schuitemaker, E. C. de Jong, and M. L. Kapsenberg
Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer
Blood,
June 1, 2001;
97(11):
3466 - 3469.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. M. Vissers, F. C. Hartgers, E. Lindhout, M. B. M. Teunissen, C. G. Figdor, and G. J. Adema
Quantitative analysis of chemokine expression by dendritic cell subsets in vitro and in vivo
J. Leukoc. Biol.,
May 1, 2001;
69(5):
785 - 793.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. H. Libraty, S. Pichyangkul, C. Ajariyakhajorn, T. P. Endy, and F. A. Ennis
Human Dendritic Cells Are Activated by Dengue Virus Infection: Enhancement by Gamma Interferon and Implications for Disease Pathogenesis
J. Virol.,
April 15, 2001;
75(8):
3501 - 3508.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Gonzalez-Juarrero and I. M. Orme
Characterization of Murine Lung Dendritic Cells Infected with Mycobacterium tuberculosis
Infect. Immun.,
February 1, 2001;
69(2):
1127 - 1133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shimizu, S.-i. Fujii, K. Fujimoto, K. Kawa, A. Yamada, and F. Kawano
Tacrolimus (FK506) treatment of CD34+ hematopoietic progenitor cells promote the development of dendritic cells that drive CD4+ T cells toward Th2 responses
J. Leukoc. Biol.,
November 1, 2000;
68(5):
633 - 640.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S.-i. Hashimoto, T. Suzuki, S. Nagai, T. Yamashita, N. Toyoda, and K. Matsushima
Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression
Blood,
September 15, 2000;
96(6):
2206 - 2214.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kalinski, H. H. Smits, J. H. N. Schuitemaker, P. L. Vieira, M. van Eijk, E. C. de Jong, E. A. Wierenga, and M. L. Kapsenberg
IL-4 Is a Mediator of IL-12p70 Induction by Human Th2 Cells: Reversal of Polarized Th2 Phenotype by Dendritic Cells
J. Immunol.,
August 15, 2000;
165(4):
1877 - 1881.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Whelan, M. M. Harnett, K. M. Houston, V. Patel, W. Harnett, and K. P. Rigley
A Filarial Nematode-Secreted Product Signals Dendritic Cells to Acquire a Phenotype That Drives Development of Th2 Cells
J. Immunol.,
June 15, 2000;
164(12):
6453 - 6460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Kiertscher, J. Luo, S. M. Dubinett, and M. D. Roth
Tumors Promote Altered Maturation and Early Apoptosis of Monocyte-Derived Dendritic Cells
J. Immunol.,
February 1, 2000;
164(3):
1269 - 1276.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Helfand, E. B. Dickerson, K. L. Munson, and M. L. Padilla
GD3 Ganglioside Antibody Augments Tumoricidal Capacity of Canine Blood Mononuclear Cells by Induction of Interleukin 12
Cancer Res.,
July 1, 1999;
59(13):
3119 - 3127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Baldini, I. Carla Lohman, M. Halonen, R. P. Erickson, P. G. Holt, and F. D. Martinez
A Polymorphism* in the 5' Flanking Region of the CD14 Gene Is Associated with Circulating Soluble CD14 Levels and with Total Serum Immunoglobulin E
Am. J. Respir. Cell Mol. Biol.,
May 1, 1999;
20(5):
976 - 983.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A. L. Zarling, J. G. Johnson, R. W. Hoffman, and D. R. Lee
Induction of Primary Human CD8+ T Lymphocyte Responses In Vitro Using Dendritic Cells
J. Immunol.,
May 1, 1999;
162(9):
5197 - 5204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kalinski, J. H. N. Schuitemaker, C. M. U. Hilkens, E. A. Wierenga, and M. L. Kapsenberg
Final Maturation of Dendritic Cells Is Associated with Impaired Responsiveness to IFN-{gamma} and to Bacterial IL-12 Inducers: Decreased Ability of Mature Dendritic Cells to Produce IL-12 During the Interaction with Th Cells
J. Immunol.,
March 15, 1999;
162(6):
3231 - 3236.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.G. Begley and N.A. Nicola
Resolving Conflicting Signals: Cross Inhibition of Cytokine Signaling Pathways
Blood,
March 1, 1999;
93(5):
1443 - 1447.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Stumbles, J. A. Thomas, C. L. Pimm, P. T. Lee, T. J. Venaille, S. Proksch, and P. G. Holt
Resting Respiratory Tract Dendritic Cells Preferentially Stimulate T Helper Cell Type 2 (Th2) Responses and Require Obligatory Cytokine Signals for Induction of Th1 Immunity
J. Exp. Med.,
December 7, 1998;
188(11):
2019 - 2031.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kalinski, J. H. N. Schuitemaker, C. M. U. Hilkens, and M. L. Kapsenberg
Prostaglandin E2 Induces the Final Maturation of IL-12-Deficient CD1a+CD83+ Dendritic Cells: The Levels of IL-12 Are Determined During the Final Dendritic Cell Maturation and Are Resistant to Further Modulation
J. Immunol.,
September 15, 1998;
161(6):
2804 - 2809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Flynn, K.-M. Toellner, C. Raykundalia, M. Goodall, and P. Lane
CD4 T Cell Cytokine Differentiation: The B Cell Activation Molecule, OX40 Ligand, Instructs CD4 T Cells to Express Interleukin 4 and Upregulates Expression of the Chemokine Receptor, Blr-1
J. Exp. Med.,
July 20, 1998;
188(2):
297 - 304.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Ahuja, S. Mummidi, H. L. Malech, and S. K. Ahuja
Human Dendritic Cell (DC)-Based Anti-Infective Therapy: Engineering DCs to Secrete Functional IFN-{gamma} and IL-12
J. Immunol.,
July 15, 1998;
161(2):
868 - 876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Rieser, C. Papesh, M. Herold, G. Bock, R. Ramoner, H. Klocker, G. Bartsch, and M. Thurnher
Differential Deactivation of Human Dendritic Cells by Endotoxin Desensitization: Role of Tumor Necrosis Factor-alpha and Prostaglandin E2
Blood,
May 1, 1998;
91(9):
3112 - 3117.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract