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*
Section of Immunobiology, Yale University School of Medicine, and
Howard Hughes Medical Institute New Haven, CT 06520;
Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, IN 46285; and
§
Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and TNF-ß. In contrast, Th2
CD4+ T cells are characterized by the production
of IL-4, IL-5, IL-9, IL-10, and IL-13, which promote some forms of
humoral immunity (notably the generation of IgG1 and IgE isotypes) and
allergic-type responses. There is also strong cross-regulation between
the two Th subsets, which, under some circumstances, can result in the
dominance of one of the two subsets and therefore a bias toward one
type of immune response. This has best been demonstrated in a variety
of pathogenic infections, including leishmaniasis, schistosomiasis and
leprosy (reviewed in Ref. 2). Infection using the protozoal parasite Leishmania major provides an ideal model for studying the induction of Th1 vs Th2 responses because resistance to infection depends on a strong Th1 response (3). Most laboratory strains, such as C57BL/6 (B6)4 and C3H, mount the strong Th1-type responses that are associated with clearance of the parasites and resolution of infection. In contrast, strains such as BALB/c are biased toward Th2-type responses, making them susceptible to the infection. Several studies suggest that this susceptibility is likely due to a burst of IL-4 production by activated Ag-specific CD4+ T cells early in the course of infection, promoting Th2 differentiation (3). Cytokines produced by Th2 cells have been shown to abrogate the initiation of macrophage activation, required for clearance of L. major infections (4). Moreover, when overexpressed in vivo, Th2 cytokines render mice of a resistant genetic background susceptible (5).
Polarized differentiation of CD4+ T cells toward
one Th subset over the other can be influenced by a number of factors,
including the cytokine environment, priming Ag dose, Ag/TCR interaction
affinity, and costimulatory signals (reviewed in Refs. 6, 7). The molecular mechanisms by which these factors orchestrate
Th cell differentiation is still unclear, but one can postulate that
they must converge at intracellular signaling molecules, which in turn
modulate the activity of transcription factors responsible for cytokine
gene expression (7, 8). c-Jun N-terminal kinase (JNK),
which phosphorylates c-Jun and enhances AP-1 transcriptional activity,
is a candidate for such signal integration (9). JNK and
AP-1 activation in T cells has been originally shown to require both
TCR/CD3 and the costimulatory molecule CD28 (10, 11). In
addition, AP-1 has been reported to be important for the regulation of
Th1 and Th2 cytokine genes (12). To address the function
of JNK in helper T cell differentiation, we have recently generated and
analyzed Jnk1-deficient mice. Quite surprisingly, in
vitro-activated Jnk1-/- naive Th cells
preferentially differentiated into Th2 cells, whereas wild-type cells
became mostly Th1 cells (13). This phenomenon was likely
caused by increased IL-4 production in response to anti-CD3
stimulation. An enhancement in Th2 responses was also seen in
Jnk1-/- effector cells primed either in
vitro by polyclonal activation or in vivo by immunization with keyhole
limpet hemocyanin in alum (13). Interestingly, we found
that Jnk1-/- Th cells remained capable of
Th1 differentiation and IFN- production in the presence of an
environment polarizing toward Th1. However, the in vitro-differentiated
Jnk1-/- Th1 populations also made
detectable amounts of Th2 cytokines, indicating a failure to
down-regulate Th2 responses. Thus, JNK1 may serve as a negative
regulator of Th2 cytokine expression (13).
To assess the role of JNK1 in regulation of in vivo immune responses, in the current study, we examined the physiological consequences of an L. major infection in Jnk1-/- mice on a Th1-biased 129 x B6 MHCb background. We found that, unlike wild-type 129 x B6 or B6 mice, Jnk1-/- mice were unable to resolve the infection. Although these mice could initiate anti-Leishmania Th1 responses to some extent, they also displayed an enhanced Th2 response. These results indicate that inhibition of Th2 cytokine production by JNK1 is an essential regulatory mechanism that ensures Th1-polarized reaction and immunity against intracellular pathogens, such as L. major.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The Jnk1-deficient and wild-type control mice were generated as described previously (13) and were maintained as homozygotes on a 129 x B6 F2 genetic background. C57BL/6 and BALB/c mice were purchased from the National Cancer Institute (Frederick, MD).
Parasites and infection protocol
L. major promastigotes of the WR309 substrain were maintained at 23°C in Schneider’s Drosophila Medium (Life Technologies, Grand Island, NY) supplemented with 20% FCS and 50 µg/ml gentamicin. Inoculates of the parasites were passaged through BALB/c mice every fifth culture split to maintain infectivity. For experiments, mice were infected in the right hind foot with 2 x 106 stationary phase promastigotes in 10 µl PBS. The course of infection in each group of mice was monitored by weekly measurements of footpad thickness of the infected right vs uninfected left foot using spring-loaded calipers. Feet were also monitored for lesion formation and ulceration.
Induction and measurement of delayed-type hypersensitivity (DTH) responses
L. major lysate was prepared by subjecting stationary phase promastigotes in PBS to two rounds of 1-min sonication, followed by filter sterilization. Protein content of lysate batches was determined by 280:260 nm spectrophotometry. Mice were challenged at 6 wk postinfection in the uninfected left foot with 40 µg of the lysate in 10 µl PBS, and footpad thickness was measured after 48 h using spring-loaded calipers.
Assaying for Leishmania-specific serum Ig
At 7–8 wk postinfection, mice were sacrificed and blood isolated by cardiac puncture. Serum was separated by centrifugation of blood samples at 2000 rpm for 5 min and then frozen at -20°C until used. For assays, ELISA plates were coated overnight at 4°C with 10 µg/ml L. major lysate (prepared as described above) in borate saline buffer, pH 8.4. Serum samples, starting at a 1:50 dilution, were diluted down in two-fold increments in borate saline buffer containing 1% BSA and 0.1% Tween 20 and incubated for 1 h at 37°C. All subsequent ELISA steps were conducted for 1 h at 37°C in borate saline buffer containing 1% BSA. Detection of IgG2a, IgG1, or IgE isotypes was conducted using biotinylated anti-Ig purchased from PharMingen (San Diego, CA) for IgG2a and IgG1, and from Biosource (Camarillo, CA) for IgE. Allotypic differences between B6 mice vs 129 x B6 and BALB/c mice was taken into account, with anti-Ig reagents of the appropriate specificity for the different strains. ELISAs were developed using HRP-streptavidin (Zymed, San Francisco, CA) followed by a tetramethylbenzidine one-step substrate system (Dako, Carpinteria, CA). Color development was stopped using 6 M HCl and plates then read at 450 nm using an EL340 automated microplate reader (Bio-Tek Instruments, Winooski, VT).
In vitro restimulation of lymph node cells
At 4 wk postinfection, mice were sacrificed and their popliteal and inguinal lymph nodes isolated and pooled. Cell suspensions were prepared and set up at 8 x 106/ml in 24-well tissue culture plates in the presence of different concentrations of L. major lysate (prepared as described above). All cultures were set up in Click’s Medium (Life Technologies) supplemented with 5% FCS. Supernatants were collected for cytokine analysis after 4 days of culture.
Stimulation of IL-12 production by macrophages and dendritic cells
For macrophage experiments, mice were injected i. p. with 1.5 ml
thioglycolate (3% in PBS) and 3 days later peritoneal macrophages were
harvested and cultured overnight in tissue culture plates at 4 x
106/ml in Click’s Medium plus 5% FCS. The
following day, nonadherent cells were removed and the remaining
adherent macrophages incubated in the presence or absence of
recombinant IFN- (10 U/ml) plus LPS (10 ng/ml). For dendritic cell
experiments, spleen cells were incubated at 37°C at
107/ml in medium plus 5% FCS in 100-mm tissue
culture petri dishes and 2 h later the nonadherent cells were
removed by washing the plates with warm medium. The remaining adherent
cells were cultured overnight and the following day the loosely
adherent dendritic cells were collected by gentle pipetting. This
typically yields populations of dendritic cells enriched to 80–85%.
Suspensions of dendritic cells were plated in 96-well microtiter plates
at 1 x 105/well in the presence of
anti-CD40L (provided by Dr. Marilyn Kehry at Boehringer Ingelheim)
at 1:100 dilution or medium alone. Supernatants from both macrophage
and dendritic cell cultures were collected 48 h later and assayed
for the presence of IL-12 p40 (see below).
Stimulation of NO2- production by macrophages
Adherent peritoneal macrophages (prepared as above) were
stimulated with either IFN- (10 U/ml) plus LPS (10 ng/ml) or plus
L. major lysate (50 µg/ml), or medium alone. Culture
supernatants were collected 48 h later and assayed for the
presence of NO2- using a
nitrate/nitrite colorimetric kit (Alexis Biochemicals, San Diego,
CA).
Assaying for cytokines in culture supernatants
Supernatants were assayed for the presence of IFN-, IL-4,
IL-5, IL-12 p40, and IL-13 cytokines using kits purchased from Endogen
(Woburn, MA) for IFN-, IL-4, and IL-5, PharMingen for IL-12, and R&D
Systems (Minneapolis, MN) for IL-13. All assays were conducted
according to manufacturers’ specifications. Concentrations of each
cytokine were calculated based on standard curves generated from
recombinant cytokines provided with the kits.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, the expected patterns of footpad
swelling were observed in susceptible BALB/c mice (a gradual increase
in lesion formation, leading to ulceration of the lesions by 7 wk
postinfection) and resistant B6 and 129 x B6 mice (an initial
small increase in lesion formation followed by a plateau in response).
Strikingly, however, the pattern of lesion formation in
Jnk1-/- mice was almost identical with
that observed in the BALB/c strain, with lesions becoming ulcerated by
7 wk postinfection. These data clearly show that, despite their
resistant genetic background, Jnk1-/-
mice are impaired in their ability to resolve a L. major
infection. This in turn suggested that JNK1 is required to make an
appropriate immunological response to clear the infection.
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shows the DTH induced by antigenic
challenge in Jnk1-/- mice as compared
with similarly treated 129 x B6, B6, and BALB/c mice. Both
129 x B6 and B6 groups show strong levels of DTH, associated with
their ability to resolve L. major infections. In comparison,
both BALB/c and Jnk1-/- mice show a
markedly reduced level of DTH, although the deficiency was more
pronounced in the susceptible BALB/c. These data suggest that
Jnk1-/- mice have an intermediate
phenotype with regards to their ability to mount efficient Th1-mediated
DTH responses. Despite this, based on the results observed in Fig. 1
, it seems likely that such reduced DTH responses are not sufficient to
completely resolve L. major infections.
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and 2 suggested that
Leishmania-infected Jnk1-/-
mice were impaired in type I immune functions. Control and clearance of
L. major infections requires effective macrophage
activation, with the production of nitric oxide
(NO2-) mediating parasite
destruction. To assess whether macrophages from
Jnk1-/- mice might have some primary
defect in their ability to produce
NO2-, which could account for
their failure to resolve an ongoing infection, we measured levels of
NO2- release following
different types of stimulation. As shown in Fig. 3, macrophages from
Jnk1-/- were as competent as macrophages
isolated from wild-type control mice to produce
NO2-, suggesting no primary
defect in their function.
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. As shown in Fig. 4, the
macrophages from Jnk1-/- mice did not
have any impairment in their capacity to produce IL-12 following
stimulation. In fact, they produced higher amounts of IL-12 than the
wild type. Dendritic cells are the other major source of IL-12 in vivo.
It has been suggested that, during Leishmania infection,
these cells make IL-12 in response to CD40 ligation by T cells.
Therefore, we isolated splenic dendritic cells from control or knockout
animals and activated them with CD40 ligand. Similar to our results
with macrophages, Jnk1-/- dendritic cells
were not defective in producing IL-12 (Fig. 4). These results indicate
that the JNK1 signaling pathway is not required for the activation of
IL-12 expression. Interestingly, we have previously shown that the p38
pathway, acting through MKK3 MAP kinase kinase, plays a major role in
IL-12 induction in both macrophages and dendritic cells
(16). Therefore, it seems unlikely that the failure of
Jnk1-/- mice to resolve their infection
is in the APC compartment at the level of either IL-12 production or
effector function.
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). Whereas all groups of mice produced
Leishmania-specific IgG2a, the Th2-dependent IgG1 isotype
was detected in only BALB/c and Jnk1-/-
mice, albeit at a reduced titer in the latter. This suggests that the
Jnk1-/- mice have enhanced Th2-type
responses relative to their 129 x B6 wild-type counterparts.
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).
Lymph node cells draining the site of a 4-wk infection in
Jnk1-/-, 129xB6, and BALB/c mice were
restimulated in vitro with L. major lysate and 4 days later
culture supernatants were assayed for the presence of various
cytokines. Jnk1-/- cells produced IFN-
at the same level as wild-type cells, whereas only half the amount was
generated by BALB/c cells. This, together with normal IgG2a titers,
suggests that Th1 effector cell development in vivo is normal in
Jnk1-/- mice. When we measured cytokines
usually associated with Th2-type responses, we found IL-5 and IL-13
were selectively produced by BALB/c and
Jnk1-/- cells (Fig. 6). This is
consistent with our previous report that in vitro-differentiated
Jnk1-/- Th1 populations also produced
detectable levels of Th2 cytokines (13). This suggests
that strong Th2 responses were induced in
Jnk1-/- mice following in vivo infection,
supporting our earlier hypothesis that JNK1 is not required for Th1
differentiation, but negatively regulates Th2 cytokine production.
Interestingly, whereas BALB/c mice produced high levels of IL-4,
Jnk1-/- cells produced only very small
amounts of the cytokine. These findings correlate with our previous
observations following in vivo immunization in
Jnk1-/- mice using keyhole limpet
hemocyanin in alum, where T cells made five-fold more IL-5, but only
30% more IL-4, than wild-type cells after the in vitro restimulation
of draining lymph node cells (13). Although our current
and previous observations agree well with regard to patterns of
cytokine production, the virtual absence of an enhancement in IL-4
production in the cultures derived from
Jnk1-/- mice is difficult to explain in
the light of Ag-specific IgG1 being detected in their serum (Fig. 5).
It is possible that IL-4 is being produced initially at higher levels
during in vitro restimulation but that the cytokine is being reused
over time. In other words, Jnk1-/- cells
may not be able to sustain IL-4 expression during restimulation. In
support of this, we were able to detect higher levels of the cytokine
when culture supernatants were sampled after only 3, instead of 4, days
of culture (S.C. and C.D., unpublished observations). However, it
should also be emphasized that the virtual absence of IL-4 in cultures
of restimulated lymph node cells does not necessarily correlate with an
absence of the cytokine during an ongoing infection in vivo. Even if
only low levels of IL-4 are produced in vivo, these may be sufficient
to induce class switching to the IgG1 isotype (17).
Interestingly, it has been shown that IL-13, although not capable of
inducing class switching in B cells directly, can act on B cells to
increase their survival and hence Ab production (18). When
we examined our culture supernatants for the presence of IL-13, we were
able to detect high levels both in the BALB/c and
Jnk1-/- but not the wild-type groups, so
it is also possible that in vivo this cytokine would help amplify any
small induction of Leishmania-specific IgG1 in
Jnk1-/- mice. In support of this
hypothesis, IL-13 transgenic mice on a B6 genetic background were
reported recently to be defective in mounting an effective immunity
against L. major (19). Moreover, several groups
have now shown that IL-4R
-deficient BALB/c mice are able to resist
L. major infections (20, 21).
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Taken together, the data suggest that Jnk1-/- mice exhibit a strikingly enhanced Th2 response following infection by L. major, although this phenotype is not as extreme as that induced in infected BALB/c mice. Because Th1-associated responses can also be detected during the course of infection, this argues against a failure of Th1 cells to develop into Jnk1-/- mice, in agreement with our earlier published observations (13). Instead, it is likely that any ongoing Th1-type immune responses are being down-modulated by the simultaneous production of Th2 cytokines, most notably IL-13, and potentially, IL-10. This study strongly supports the hypothesis that JNK1 is involved in the negative regulation of Th2 cytokine production, and further demonstrates that the negative regulation of Th2 responses by JNK1 plays an indispensable role in generation of a Th1-polarized reaction during L. major infection in mice of a resistant (Th1-dominant) genetic background.
We have previously shown that there is an enhancement of NF-ATc nuclear accumulation in Jnk1-/- cells in response to anti-CD3 stimulation, independent of IL-4 (13). Recently, we have identified the biochemical mechanism by which JNK1 regulates NF-ATc nuclear localization (23). JNK1 can bind to and phosphorylate NF-ATc, which then inhibits targeting of calcineurin phosphatase. Mutation of two serine residues that are phosphorylated by JNK to alanine rendered constitutive nuclear localization of NF-ATc molecules. NF-ATc has been shown to bind the IL-4 promoter and to be essential for Th2 development and cytokine production (24, 25). Interestingly, NF-ATc mutant molecules that are constitutively nuclear could activate a minimal IL-4 promoter reporter (23), suggesting that greatly enhanced nuclear accumulation of NF-ATc in activated JNK1-deficient T cells might account for the exacerbated production of Th2 cytokines by these cells. Knockout mice for NF-ATp, another member of the NF-AT family, show a strikingly similar phenotype to Jnk1-/- mice (26, 27). These mice, also on a 129 x B6 background, were reported to be susceptible to L. major infection (26). Thus, NF-ATc and NF-ATp, both of which can bind to the IL-4 promoter (28), may antagonize each other in regulating Th2 cytokine production. JNK1, by regulating NF-ATc nuclear localization, may modulate the balance of this Yin-Yang pair and therefore the outcome of immunity. The results presented here clearly demonstrate that JNK1 is essential for protective in vivo Th1 responses and immunity against L. major through the inhibition of Th2 responses.
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Acknowledgments |
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Footnotes |
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2 S.L.C. and C.D. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Richard A. Flavell, Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, FMB 412, P.O. Box 208011, New Haven, CT 06520-8011.
4 Abbreviations used in this paper: B6, C57BL/6; JNK, c-Jun N-terminal kinase; DTH, delayed-type hypersensitivity.
Received for publication March 20, 2000. Accepted for publication June 16, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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from host-protective T cells is inhibited by interleukin (IL) 3 and IL 4 produced by disease-promoting T cells in leishmaniasis. Eur. J. Immunol. 19:1227.[Medline]
-deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162:7302.This article has been cited by other articles:
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  Y. Y. Wan and R. A. Flavell How Diverse--CD4 Effector T Cells and their Functions J Mol Cell Biol, October 1, 2009; 1(1): 20 - 36. [Abstract] [Full Text] [PDF]
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 A. Saadeddin, R. Babaei-Jadidi, B. Spencer-Dene, and A. S. Nateri The Links between Transcription, {beta}-catenin/JNK Signaling, and Carcinogenesis Mol. Cancer Res., August 1, 2009; 7(8): 1189 - 1196. [Abstract] [Full Text] [PDF]
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 G. Adhikary, Y. Sun, and E. Pearlman C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation J. Leukoc. Biol., April 1, 2008; 83(4): 991 - 997. [Abstract] [Full Text] [PDF]
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 W. Sukhumavasi, C. E. Egan, and E. Y. Denkers Mouse Neutrophils Require JNK2 MAPK for Toxoplasma gondii-Induced IL-12p40 and CCL2/MCP-1 Release J. Immunol., September 15, 2007; 179(6): 3570 - 3577. [Abstract] [Full Text] [PDF]
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W. Lim, K. Gee, S. Mishra, and A. Kumar Regulation of B7.1 Costimulatory Molecule Is Mediated by the IFN Regulatory Factor-7 through the Activation of JNK in Lipopolysaccharide-Stimulated Human Monocytic Cells J. Immunol., November 1, 2005; 175(9): 5690 - 5700. [Abstract] [Full Text] [PDF]
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Y. Yang, J. Ochando, A. Yopp, J. S. Bromberg, and Y. Ding IL-6 Plays a Unique Role in Initiating c-Maf Expression during Early Stage of CD4 T Cell Activation J. Immunol., March 1, 2005; 174(5): 2720 - 2729. [Abstract] [Full Text] [PDF]
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K. Gee, W. Lim, W. Ma, D. Nandan, F. Diaz-Mitoma, M. Kozlowski, and A. Kumar Differential Regulation of CD44 Expression by Lipopolysaccharide (LPS) and TNF-{alpha} in Human Monocytic Cells: Distinct Involvement of c-Jun N-Terminal Kinase in LPS-Induced CD44 Expression J. Immunol., November 15, 2002; 169(10): 5660 - 5672. [Abstract] [Full Text] [PDF]
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W. Lim, W. Ma, K. Gee, S. Aucoin, D. Nandan, F. Diaz-Mitoma, M. Kozlowski, and A. Kumar Distinct Role of p38 and c-Jun N-Terminal Kinases in IL-10-Dependent and IL-10-Independent Regulation of the Costimulatory Molecule B7.2 in Lipopolysaccharide-Stimulated Human Monocytic Cells J. Immunol., February 15, 2002; 168(4): 1759 - 1769. [Abstract] [Full Text] [PDF]
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N. Arbour, D. Naniche, D. Homann, R. J. Davis, R. A. Flavell, and M. B.A. Oldstone c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Signaling Pathways Have Divergent Roles in CD8+ T Cell-mediated Antiviral Immunity J. Exp. Med., March 25, 2002; 195(7): 801 - 810. [Abstract] [Full Text] [PDF]
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D. Conze, T. Krahl, N. Kennedy, L. Weiss, J. Lumsden, P. Hess, R. A. Flavell, G. Le Gros, R. J. Davis, and M. Rincon c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation J. Exp. Med., March 25, 2002; 195(7): 811 - 823. [Abstract] [Full Text] [PDF]
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