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Kali
ski2,*
*
Department of Cell Biology and Histology and
Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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, IL-4
strongly enhances the production of bioactive IL-12p70 heterodimer in
CD40 ligand-stimulated DC and macrophages and synergizes with IFN-
at low concentrations of both cytokines. However, in contrast to
IFN-, IL-4 inhibits the CD40 ligand-induced production of inactive
IL-12p40 and the production of either form of IL-12 induced by LPS,
which may explain the view of IL-4 as an IL-12 inhibitor. The presently
described ability of IL-4 to act as a cofactor of Th cell-mediated
IL-12p70 induction may allow Th2 cells to support cell-mediated
immunity in chronic inflammatory states, including cancer,
autoimmunity, and atopic dermatitis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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(2), a product of Th1 cells,
CD8+ T cells, and NK cells. Primary polarization of Th cells occurs already at the moment of their priming in the lymph nodes (3). Although DC are the only APC type involved in priming of naive Th cells, other APC types, e.g., B cells, are involved in regulating the cytokine profiles of Th cell responses (4, 5). This indicates the importance of postpriming events in the modulation of cytokine profiles in committed Th cells, which mechanism is not completely clarified yet.
Compared with their mouse counterparts, human Th2 cells are more
flexible and susceptible to the reversal of their polarized cytokine
profiles by exogenous IL-12 (6), suggesting the
possibility of their therapeutic remodulation, e.g., in Th2-mediated
disorders. However, because committed Th2 cells are deficient in
IFN- production and produce endogenous Th2-driving factors, e.g.,
IL-4, that were shown to suppress IL-12 production (7, 8, 9),
it remains unclear whether and in which conditions such a reversal can
also occur in physiologic situations. Here we show that although, in
accordance with previous studies, IL-4 is an inhibitor of LPS-induced
IL-12 production (7, 9) and an inhibitor of CD40L-induced
production of inactive IL-12p40 subunit (8), it is a
potent enhancer of the production of bioactive IL-12p70 heterodimer in
DC and macrophages, allowing human Th2 cells to efficiently induce
IL-12p70.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Generation of polarized Th cell populations was performed in
IMDM supplemented with 5% normal human serum (BioWhittaker,
Walkersville, MD), gentamicin (80 mg/ml; Duchefa, Haarlem, The
Netherlands) and rIL-2 (10 U/ml; Chiron, Emeryville, CA).
CD45RA+-naive CD4+ Th cells were
isolated (purity >98%) from PBMC of healthy donors using negative
selection columns (R&D Systems Europe, Abingdon, U.K.). Th cells were
stimulated with immobilized CD3 mAb (1 µg/ml, CLB-T3/3; The Central
Laboratory of Blood Transfusion Service (CLB), Amsterdam, The
Netherlands) and soluble CD28 mAb (2 µg/ml, CLB-CD28/1; CLB) and
cultured for 10 days in the presence of either rIL-4 (1000 U/ml; Pharma
Biotechnologie, Hannover, Germany), for Th2-polarizing conditions, or
rIL-12 (100 U/ml; a gift from Dr. M. K. Gately, Hoffman-La
Roche, Nutley, NJ) and neutralizing anti-IL-4 (1 µg/ml;
CLB-IL-4/6 (5B5), CLB), for Th1 polarizing conditions. House dust
mite-specific Th2 clone (RDC41), isolated from peripheral blood of an
atopic patient and selected on the basis of its strongly pronounced
deficit in IL-12 responsiveness and a total inability to produce
IFN-, was described previously (10).
DC and macrophages
To obtain immature DC, monocytes (5 x 105 cells/ml) were cultured for 6 days in 24-well plates (Costar, Cambridge, MA) in IMDM with 10% FCS (HyClone, Logan, UT) and gentamicin (80 µg/ml; Duchefa) supplemented with recombinant human (rhu) GM-CSF (500 U/ml; a gift of Schering-Plough, Uden, The Netherlands) and rhuIL-4 (250 U/ml; Pharma Biotechnologie), as described (2, 11). At day 6, the cultures consisted of uniformly HLA-DR+, CD83-, and CD40high immature DC, without detectable CD3+ cells. Over 90% of the cells expressed high levels of CD1a. Macrophages were obtained in parallel GM-CSF-supplemented cultures that did not contain IL-4, as described (2). They showed CD14 expression, lack of CD1a, and lower levels of CD80, CD86, and CD40 expression, in accordance with a previous report (2). Cell-surface phenotype was analyzed by flow cytometry, after labeling of cells with appropriate mAb as described (2, 11).
B cells
Peripheral blood B cells were isolated using the StemSep Ab enrichment cocktail (StemCell Technologies, Vancouver, Canada) for human B cells in combination with StemSep magnetic colloid, according to the manufacturer’s instructions. Isolated B cells (>95% positive for CD20, <1% for CD3, <1% for CD14, <1% for CD16) were cultured overnight before irradiation (2500 Gy) and coculture with Th cells.
APC-Th cell cocultures
At day 12 after priming in either Th1- or Th2-driving
conditions, Th cells were harvested, washed, and cocultured
(105 cells per well) with DC (2 x
104) or B cells (6 x
104) in the presence of staphylococcal
enterotoxin B (SEB; 1 ng/ml; Serva, Heidelberg, Germany) in a final
volume of 0.2 ml, as described (2, 11). When indicated,
rhuIL-12 (100 U/ml) was added at the beginning of the cocultures. To
test the impact of the interaction of Th2 cells with different APC
populations upon their subsequent cytokine profile, such differentially
restimulated Th2 cells were expanded for an additional 8 days before
their tertiary stimulation with PMA/ionomycin. To compare the
IL-12p70-inducing capacity of Th1 and Th2 cells, they were cocultured
(105 cells per well in 0.2 ml) for 48 h with
DC (2 x 104) or B cells (6 x
104) in the presence of SEB. To study the
induction of IL-12p70 by a totally IFN--deficient Th2 clone (RDC41)
(10), a model was used where DC presented a stimulatory
mouse anti-human CD3 mAb (IgG2a) via FcgR (12). Some
cultures contained 1 mg/ml of IL-4-neutralizing mAb (CLB-IL-4/6) or
control-irrelevant mouse IgG1 (DL-5, a gift from Dr. P. H. van der
Meide, Biomedical Primate Research Centre, Rijswijk, The
Netherlands) as indicated.
Th cell-independent DC stimulation
DC were washed and stimulated (2 x
104 cells in 200 µl) with one of the following
stimuli: CD40L-transfected J558 plasmacytoma cells (J558-CD40L, 5
x 104 cells per well; a gift from Dr. P. Lane, Birmingham
Medical School, Birmingham, U.K.), which were previously shown to
induce IL-12p70 in an IFN--independent way (13),
soluble recombinant CD40L trimer (sCD40L, 1 µg/ml; a gift from Dr.
E. K. Thomas, Immunex, Seattle, WA), known to require IFN- to
induce high-level IL-12p70 production, in analogy to CD40L expressed on
Th cells (2, 11), or with LPS (250 ng/ml; Difco, Detroit,
MI). RhuIFN- (a gift from Dr. P. H. van der Meide) or rhuIL-4
were added to the cultures as indicated.
Cytokine measurements
Analysis of Th cell cytokine production at a single-cell basis
was performed after 6-h stimulation with PMA (10 ng/ml, Sigma, St.
Louis, MO) and ionomycine (1 mg/ml; Sigma) in the presence of Brefeldin
A (10 µg/ml; Sigma). The cells were fixed with 2%
paraformaldehyde, permeabilized with 0.5% saponine (Sigma), and
labeled with FITC-coupled IFN- mAb (Becton Dickinson, Mountain View,
CA) and PE-coupled IL-4 mAb (Becton Dickinson). The cells were
evaluated by FACScan (Becton Dickinson). IL-12 p70 ELISA (sensitivity,
3 pg/ml) (9) was performed with the use of p70-specific
mAb 20C2 (a gift from Dr. M. K. Gately) and p40-specific C8.6 mAb
(a gift from Dr. G. Trinchieri, Wistar Institute, Philadelphia, PA).
IL-12p40-, IFN--, and IL-4-specific ELISAs were described before
(2, 9, 11, 14).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Priming of human naive Th cells in the presence of IL-4 yielded
strongly polarized human Th2 cells that produced IL-4 but not the
Th1-type cytokine IFN- (Fig. 1
A, left). Although
B cells and DC are both efficient APC for memory Th cells, the
restimulation by these distinct APC populations yielded different
outcomes for the cytokine profiles of such committed Th2 cells. Th2
cells restimulated by B cells preserved their polarized Th2 cytokine
profiles, as evidenced by their selective production of IL-4 but not
IFN- after a subsequent, tertiary stimulation (Fig. 1A,
top, Fig. 1B). The presence of exogenous IL-12p70
during the B cell-mediated restimulation of Th2 cells shifted their
cytokine profiles, resulting in Th0/Th1-type cells, producing IFN-
upon subsequent stimulation. These findings are in line with the
previous observations that human Th2-polarized cells are more flexible
than their mouse counterparts and can revert to Th0/Th1-like cells in
response to exogenous IL-12 (6), becoming resistant to
IL-12 only in a fraction of terminally polarized clones
(10). The mechanism of reversal of Th2 phenotype within
polarized Th cell population and the definition of the
point-of-no-return for individual Th2-biased human cells need further
analysis at the clonal level.
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A, bottom, Fig. 1B), indicating the intrinsic tendency of Th2 cells to
revert to Th0/Th1-type cells following the interaction with DC. The
addition of exogenous IL-12p70 to DC-restimulated Th2 cell cultures did
not have any additional effect (Fig. 1A,
bottom-right). Th2 cells effectively induce IL-12p70 production in an IL-4-dependent mechanism
The above findings suggested a possibility that endogenous
IL-12p70 production was induced during Th2 cell-DC interaction. Indeed,
cocultures of Th2 cells with DC (but not with B cells) resulted in the
production of surprisingly similar amounts of IL-12p70 as the DC-Th1
cocultures (Fig. 2A). This was
accompanied by the onset of IFN- production in Th2-DC cocultures
visible already within 48 h (not shown). To test whether the
IL-12-inducing capacity is also present in Th2 cells devoid of any
residual ability to produce IFN-, we used an IL-12-unresponsive Th2
clone generated from an atopic patient (RDC41) that was totally
deficient in IFN- production (10). In contrast to naive
Th cells that induce only trace amounts of IL-12p70 due to their low
IFN- production (2), the RDC41 clone proved itself as
an efficient IL-12p70 inducer (Fig. 2B), despite the fact
that it selectively produced high IL-4 levels during the stimulation
with CD3 and CD28 mAb (1.2 ± 0.09 ng/ml) and during the
interaction with DC (2.81 ± 0.04 ng/ml) but not any detectable
IFN- (<70 pg/ml) both after the CD3/CD28 mAb stimulation and during
the 48-h interaction with DC. This suggested that 1) the ability of
human Th2 cells to induce IL-12 is not restricted to the situations
when their IL-4 production is low, as proposed before
(15), but is a standard phenomenon, and 2) that human Th2
cells use a separate, different from IFN-, costimulatory mechanism
that provides them with the ability to induce IL-12p70 production. In
support of this possibility, neutralization of IL-4 in Th2 cell-DC
cocultures resulted not in an enhancement but in a profound suppression
of IL-12p70 production (Fig. 2B), indicating that IL-4
produced during the Th2 cell-DC interaction acts as a Th2 cell-specific
costimulatory factor for the induction of IL-12p70 instead of being an
IL-12 inhibitor. The key role of IL-4 in the induction of IL-12p70
production by Th2 cells signifies that this ability is intrinsic to
polarized Th2 phenotype.
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To confirm this unexpected activity of IL-4 in a more simple
model, DC were stimulated with J558-CD40L, which are known to induce
substantial IL-12p70 production already in the absence of any
additional factors (13). Indeed, also in this model IL-4
dose-dependently increased the production of bioactive IL-12p70, with a
similar efficacy as IFN- (Fig. 3A). However, while the IL-12
p70-enhancing activity of IFN- was accompanied by the enhancement of
an overall IL-12p40 production (mostly composing an inactive p40-p40
homodimer) (1), the elevation of IL-12p70 production by
IL-4 was accompanied by a dose-dependent suppression of p40 production.
This reciprocal regulation of the two IL-12 subunits by IL-4 indicates
that IL-12p40 is a poor marker of bioactive IL-12 production. In
contrast to the IL-12p70 heterodimer, the p40 homodimer, produced in
huge excess over IL-12p70, lacks the biological activity of IL-12 and
can act as a competitive IL-12 inhibitor (1).
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B) that show lower CD40 expression than
DC (2), current data not shown) and lower overall levels
of IL-12p70 production after CD40L triggering. In addition, IL-4 showed
a synergism with IFN- in costimulating the IL-12p70 production in
J558-CD40L-stimulated macrophages at low, perhaps more physiological,
concentrations of these cytokines (Fig. 3C, top).
A similar synergism between low concentrations of IL-4 and IFN-
could be observed in DC, especially after their stimulation with sCD40L
(Fig. 3C, bottom), which provides a weaker
IL-12-inducing signal compared with J558-CD40L (2, 11). A
requirement for both IL-4 and IFN- in the optimal induction of
IL-12p70 production may explain the surprising observation that IL-4
knockout mice show a deficit of some Th1 functions (see below),
reversible upon exogenous IL-4 treatment (16).
Despite strongly up-regulating the CD40L-induced IL-12p70 production,
IL-4 significantly inhibited the LPS-induced production of IL-12p70
(Fig. 4, p < 0.01), in
accordance with previous reports (7, 9). This differential
regulatory effect upon the IL-12p70 production induced either by CD40
ligation or by bacterial products, together with the ability of IL-4 to
inhibit the CD40L-induced production of the inactive p40 subunit of
IL-12 (see Fig. 3A; Ref. 8), may explain the
current view of IL-4 as an inhibitor of IL-12 production.
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In contrast to the view of IL-4 as an inhibitor of IL-12
production, the present findings show that IL-4 acts as a Th2-specific
coinducer of the production of bioactive IL-12p70, resulting in an
intrinsic tendency of human Th2 cells to revert to IFN--producing
Th0/Th1 phenotype upon the interaction with DC. They suggest that an
initial commitment of lymph node-based naive Th cells to the Th2 subset
results in a flexible population of effector cells, the functions of
which remain under control of distinct APC populations encountered in
peripheral tissues. This feature may allow Th2 cells to induce
different effector mechanisms of immunity depending on the requirements
met in distinct locations. The interaction with IL-12-deficient B cells
can result in helper signals for Ig production but also in a
preservation, or an enhancement, of the polarized Th2 phenotype. The
maintenance of polarized Th2 cytokine profiles can also occur when Th2
cells meet other APC populations in the tissues rich in
IL-12-suppressing factors, e.g., IL-10, TGF-ß, or
PGE2, like the mucosa of the airways and the
alimentary tract, or tumor tissues. DC isolated from the airways and
from the gut-associated lymphoid tissues have been recently shown to be
IL-12 deficient (17, 18). Repetitive (re)stimulations in
such conditions may allow Th2 cells to proceed to the stage of
IL-12-resistant Th2 cells, a phenotype observed in a small fraction of
human Th cells in atopic disease (10).
In contrast to the above situation, migration of Th2-polarized cells to
the tissues that can accommodate the potentially dangerous Th1
responses and that allow for local IL-12 production, such as the skin,
can result in encountering APC that are able to produce IL-12 in
response to CD40L- and IL-4-mediated signals. This can allow Th2 cells
to effectively contribute to the local inflammatory-type responses by
abandoning their Th2-polarized phenotype and supporting the IL-12- and
IFN--dependent mechanisms of cellular immunity.
Such a differential control of Th2 cell function by distinct tissues
and APC types may possibly be observed in pathological conditions in
atopic dermatitis. Allergen-specific Th2 cells efficiently support IgE
production in atopic individuals, consistent with the absence of
IFN- (that suppresses IgE production) (19) during their
interaction with B cells. In contrast, activation of allergen-specific
Th2 cells in the skin results in a not completely understood phenomenon
of an early wave of Th2-type cytokine production, followed by the late
phase of IL-12 and IFN- production (20). The presently
described IL-4-mediated IL-12 induction by infiltrating Th2 cells and
their resulting repolarization may explain the mechanism of this
process.
Although mouse Th2 cells, which (in contrast to their human counterparts) (6) typically produce high levels of IL-10, can suppress IL-12p70 production (21), the classical view of IL-4 and IL-10 as two equivalent Th2 cell-derived IL-12 inhibitors may need reevaluation also in the mouse system. Although earlier studies (22) showed a partial inhibitory effect of IL-4 upon the IL-12 production induced in DC by CD40 mAb, recent data obtained in a more physiological model of OVA-specific TCR-transgenic animals (21) indicated that mouse IL-4, in contrast to IL-10, lacks the IL-12p70-suppressing activity, whereas another mouse study showed the ability of IL-4 to enhance IL-12 production (23).
In accordance with a possible role of murine IL-4 as an IL-12p70
inducer, Schuler et al. (16) have recently shown that
IL-4-knockout mice have impaired tumor immunity, associated with an
impaired development of tumor-specific CTL responses, reduced
production of IFN-, and reduced levels of tumor-reactive IgG2a, the
hallmarks of impaired Th1-cell function. This deficit was reversible
upon the administration of exogenous IL-4, but the link between IL-4
deficiency and the observed phenotype remains to be established.
IL-4-deficient mice also show an impaired resistance to Candida
albicans (24) associated with impaired production of
IFN- and reduced levels of IL-12. Although the administration of
rIL-4 corrected these deficits and primed neutrophils for increased
IL-12 production, it needs to be established whether IL-4 can also
contribute to the induction of IL-12 during the interaction of APC with
C. albicans-specific T cells, because IL-4 was shown
ineffective upon peritoneal macrophages (24). Similarly,
it remains to be tested whether the IL-4-mediated induction of IL-12
plays a role in the paradoxical ability of some Th2 cells to promote
autoimmune destruction of own tissues (25, 26) and whether
it contributes to the recently described ability of IL-4 to enhance the
production of endogenous IFN- in CD40L-stimulated DC
(27).
The presently described flexibility of Th2 cells and their functional dependence on distinct APC types underline the importance of the postpriming checkpoints controlling the quality of the immune response and suggest additional possibilities of therapeutic induction of Th1 responses in Th2-associated diseases.
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Acknowledgments |
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reagents,
Dr. Kees de Groot for stimulating discussions, and Ing. Jan Wormmeester
for logistic help. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Pawe Kaliski at his current address: University of Pittsburgh, Department of Surgery, W1540 BST, 200 Lothrop Street, Pittsburgh, PA 15261.
3 Address correspondence and reprint requests to Dr. Martien L. Kapsenberg, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
4 Abbreviations used in this paper: DC, dendritic cells; CD40L, CD40 ligand; J558-CD40L, CD40L-transfected J558 plasmocytoma cells; sCD40L, soluble recombinant CD40L trimer; SEB, staphylococcal enterotoxin B; rhu, recombinant human.
Received for publication December 21, 1999. Accepted for publication June 2, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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production. J. Exp. Med. 1822:537.
and to bacterial IL-12 inducers: decreased ability of mature DC to produce IL-12 during the interaction with T helper cells. J. Immunol. 162:3231. level of activated human CD4+ T cells. J. Immunol. 5:1722.
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. J. Immunol. 136:949.[Abstract]
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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]
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X. Jiao, R. Lo-Man, P. Guermonprez, L. Fiette, E. Deriaud, S. Burgaud, B. Gicquel, N. Winter, and C. Leclerc Dendritic Cells Are Host Cells for Mycobacteria In Vivo That Trigger Innate and Acquired Immunity J. Immunol., February 1, 2002; 168(3): 1294 - 1301. [Abstract] [Full Text] [PDF]
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T. Luft, M. Jefford, P. Luetjens, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky IL-1{beta} Enhances CD40 Ligand-Mediated Cytokine Secretion by Human Dendritic Cells (DC): A Mechanism for T Cell-Independent DC Activation J. Immunol., January 15, 2002; 168(2): 713 - 722. [Abstract] [Full Text] [PDF]
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 K. Kawakami, Y. Kinjo, S. Yara, K. Uezu, Y. Koguchi, M. Tohyama, M. Azuma, K. Takeda, S. Akira, and A. Saito Enhanced Gamma Interferon Production through Activation of Valpha 14+ Natural Killer T Cells by alpha -Galactosylceramide in Interleukin-18-Deficient Mice with Systemic Cryptococcosis Infect. Immun., November 1, 2001; 69(11): 6643 - 6650. [Abstract] [Full Text] [PDF]
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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]
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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]
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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] |
