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* Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140; and
Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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priming. We speculate that
the observed difference in response of the two APC types to M.
tuberculosis infection may be a reflection of their respective
roles in immune initiation and granuloma
regulation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene exhibit deficient production of the antimycobacterial
reactive nitrogen intermediates and have defective granuloma formation;
consequently, they are highly susceptible to M. tuberculosis
infection (2, 3). IL-12, a cytokine critical for the
development of Th1 cells, is essential for protection against M.
tuberculosis in murine experimental TB models (4, 5).
In humans strong evidence for the importance of IFN- (6, 7) and IL-12 (8, 9) in host defense against
mycobacterial infection has recently emerged. The protective role of
Th1 cell-mediated immune response in TB is perhaps best illustrated by
the enhanced susceptibility to M. tuberculosis in
individuals with HIV infection, a disease characterized by profound
loss of CD4+ T cells, including the Th1 subtype
(10). Therefore, while it is well established that the
protective immune response to M. tuberculosis is dependent
on the host’s ability to initiate Th1 cellular responses, the
microenvironment essential for the development of these Th1 cells is
not well understood.
Among several factors that can regulate naive T cell polarization and
development of Th1 or Th2 type in response to infection, the APC is
perhaps the most influential. Since its initial identification as a
novel cell type in peripheral lymphoid organs of mice
(11), dendritic cells have gained acceptance as potent
APC. While macrophages and dendritic cells can both process and present
Ag to T cells, dendritic cells are unique in their ability to initiate
a primary immune response. This functional feature of the dendritic
cell is due to its high mobility and high surface expression of MHC and
costimulatory molecules. In response to antigenic stimuli, immature
dendritic cells migrate rapidly to peripheral tissue, where they
can detect, capture, and process foreign Ag. Following Ag
encounter, dendritic cells fully mature into APC, up-regulate their
chemokine receptors, and migrate into T cell-enriched areas of lymphoid
tissue. Here the Ag-loaded dendritic cells present Ag-derived peptides
associated with either class I or class II MHC molecules to naive
CD8+ and CD4+ T cells,
respectively (12, 13, 14). Dendritic cell maturation is also
regulated by proinflammatory cytokines of the innate immune response
such as TNF-
and IL-1
(13, 15, 16).
M. tuberculosis resides mainly within macrophages; however, recent studies have shown that dendritic cells can also phagocytose the bacterium (17, 18). In addition, both these APC types are present in the lung (18) and are activated following infection (19). Thus, upon infection both cell types can potentially regulate the polarization of naive T cells. Therefore, in this study we examined whether following M. tuberculosis infection dendritic cells and macrophages differed in their ability to influence the polarization of naive T cells obtained from spleens of OVA peptide TCR-transgenic mice. We demonstrate that dendritic cells infected with M. tuberculosis direct the development of naive Th cells toward the Th1 phenotype due to their potential to produce IL-12 in the presence of microbial stimuli alone. In contrast, infected macrophages do not secrete IL-12 and consequently are not capable of supporting naive T cell development toward a Th1 phenotype.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c were purchased from The Jackson Laboratory (Bar Harbor, ME). OVA peptide-specific DO11.10 TCR-transgenic mice on the BALB/c background were generated by Dr. K. Murphy (Washington University School of Medicine, St. Louis, MO) (20) and obtained from Dr. R. Seder (National Institutes of Health, Bethesda, MD). For these studies transgenic mice were bred and maintained under pathogen-free conditions at the Rodent Barrier Facility of Temple University School of Medicine (Philadelphia, PA). IL-10-deficient mice on the BALB/c background were a gift from Dr. C. A. Hunter (University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA).
Microbial stimuli
The virulent M. tuberculosis Erdman strain (Trudeau Institute, Saranac Lake, NY), obtained after mouse passage, was grown in culture, titrated, and stored in aliquots at -70°C. Before infection, aliquots were thawed, briefly sonicated, and then added to cultures at the appropriate multiplicity of infection (MOI). Escherichia coli LPS was purchased from Sigma-Aldrich (St. Louis, MO).
Macrophages and dendritic cells
Bone marrow was flushed from the femora and tibiae of mice and
cultured in DMEM/10% FCS supplemented with 20% L cell-conditioned
medium as previously described (21). Bone marrow-derived
macrophages (BMM
) were harvested on day 7. For obtaining bone
marrow-derived dendritic cells (BMDCs), bone marrow cells were cultured
at a density of 106 cells/ml in DMEM/10% FCS
supplemented with penicillin (100 U/ml), streptomycin (100 µg/ml),
glutamine (2 mM), 2-ME (5 x 10-5 M), and
750 U/ml murine rGM-CSF (R&D Systems, Minneapolis, MN). Every 2 days
one-half of the medium was removed and supplemented with fresh medium
and rGM-CSF. Nonadherent cells comprising the immature dendritic cell
population were harvested on day 7. In some experiments adherent
splenic macrophages were obtained from spleen cell suspensions by
adherence for 1 h to tissue culture-treated plates. Adherent cells
were harvested by incubation with 5 mM EDTA in
Ca2+- and Mg2+-free PBS for
10 min. The purity of each population was determined by FACS analysis
of specific surface markers and ranged from 80 to 95%.
Direct isolation of splenic dendritic cells and macrophages
Spleen cell suspensions were prepared by collagenase digestion with collagenase VII (Sigma-Aldrich) that was endotoxin free. Splenic dendritic cells were enriched by MACS with anti-CD11c magnetic beads (Miltenyi Biotec, Auburn, CA) using positive selection columns. CD11c- cells were used to isolate CD11b+ splenic macrophages by MACS with anti-CD11b magnetic beads. The enriched populations were subjected to FACS analysis for surface expression of CD11b and CD11c, and purity ranged from 80 to 95%.
Isolation of transgenic T cells
Naive transgenic T cells were isolated from the spleens of DO11.10 transgenic mice. T cells were purified by removing macrophages and B cells from spleen cell cultures by adherence to plastic, followed by adherence to nylon wool columns (Polysciences, Warrington, PA) (22). We routinely observed that >90% of the isolated T cells were CD4+.
Cytokine assays
Analysis of cytokines present in supernatants was performed by
ELISA using Ab pairs from BD PharMingen (San Diego, CA): C15.6 and
C17.8 (biotinylated) for IL-12p40, 9A5 and C17.8 (biotinylated) for
IL-12p70, JES5-2A5 and JES5-16E3 (biotinylated) for IL-10, R4-6A2 and
XMG1.2 (biotinylated) for IFN-, 11B11 and BVD6-24G2 (biotinylated)
for IL-4, and G281-2626 and MP6-XTB for TNF-.
RNase protection assays
Total RNA was isolated from cells using RNAzol B reagent (Biotecx Laboratories, Houston, TX) according to the manufacturer’s protocol. The RNase protection assay was performed using 7–10 µg total RNA and the Riboquant kit (BD PharMingen). Protected [32P]UTP-labeled probes were resolved on a 5% polyacrylamide gel, analyzed by autoradiography, and quantitated by phosphorimaging using MultiAnalyst Systems software (Bio-Rad, Hercules, CA).
Flow cytometry for IL-10R expression
IL-10R expression was measured by immunofluorescence. Cells (1 x 106) were infected with M. tuberculosis (3 MOI) in the presence of neutralizing Abs to IL-10 to minimize masking of the receptor. The cells were then stained with PE-conjugated anti-mouse IL-10R Abs (clone 1B1.3a, IgG1 isotype; BD PharMingen). An aliquot of cells also received an irrelevant Ab of the same isotype. Surface fluorescence was assayed by flow cytometry.
Statistics
For statistical analysis of samples, paired and unpaired Student’s t tests were performed (PRISM version 3.0; GraphPad, San Diego, CA); a value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We delineated the capacity of M. tuberculosis-infected
macrophages and dendritic cells to bias Ag-specific naive T cells to
effector Th1 and Th2 cells. A difficulty in studying naive T cell
differentiation is the low number of Ag-specific naive T cells present
during immune initiation. Therefore, we took advantage of the DO11.10
TCR-transgenic mice that express a TCR- specific for OVA
peptide, aa 323–339 presented on MHC molecule
I-Ad. T cells from these mice were used to study
the effect on priming by M. tuberculosis-infected dendritic
cells and macrophages.
Dendritic cells and macrophages were infected at different MOIs for
24 h. Naive T cells obtained from the spleens of transgenic mice
were allowed to differentiate in the presence of OVA peptide in an
M. tuberculosis-infected APC milieu for 72 h. T cells
were then re-exposed to Ag and APC in the absence of any biasing
modalities, and the cytokine profile of the differentiated T cells was
determined. As observed in Fig. 1
, in the
absence of any M. tuberculosis infection neither dendritic
cells nor macrophages had any polarizing effect on the differentiating
naive T cells. However, when naive T cells were allowed to
differentiate in the presence of M. tuberculosis-infected
dendritic cells they acquired Th1 polarity. In contrast, naive T cells
differentiating in the M. tuberculosis-infected macrophage
setting failed to differentiate into Th1 cells and continued to
maintain a Th0 phenotype. This differential response on T cell
polarization by dendritic cells and macrophages was seen at all three
MOIs tested (Fig. 1A).
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B). IL-12 released from dendritic cells is critical for naive T cell polarization to Th1 type
Because previous studies have determined that IL-12 is a critical
factor for Th1 cell responses (23), we consequently
examined the secreted levels of IL-12p40 from M.
tuberculosis-infected dendritic cells and macrophages. M.
tuberculosis infection of dendritic cells induced significant
levels of IL-12p40 production at all three MOIs tested. However, the
same infection level in macrophages induced very low levels of IL-12p40
(Fig. 2A). Interestingly,
parallel evaluation for TNF- levels revealed that M.
tuberculosis infection induced similar levels of this cytokine in
both dendritic cells and macrophages (Fig. 2B). These data
indicated that the interaction of M. tuberculosis and
macrophage resulted in production of the proinflammatory cytokine
TNF-, ruling out that lack of IL-12p40 production was due to lack of
signaling from macrophages. We next examined the level of bioactive
IL-12p70 and noted a similar differential response; dendritic cells
produced IL-12p70 following M. tuberculosis infection,
whereas infected macrophages did not secrete any detectable levels of
the cytokine (Fig. 2C). The difference in IL-12p40 protein
expression was also seen at the level of gene transcription (Fig. 2D). There was a 74% induction of mRNA levels for
IL-12p40 compared with housekeeping gene L32 in
dendritic cells following infection. In contrast, only a 2.2% increase
was observed in macrophages.
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A). Also as previously
observed, IL-4 production was suppressed in T cells biased under the
influence of M. tuberculosis-infected
CD11c+ dendritic cells; however, similar
suppression of IL-4 production was not observed in T cells biased under
the influence of CD11b+ macrophages (Fig. 3B). Thus, the biasing properties of BMDCs and macrophages
were replicated in the directly isolated dendritic cells and
macrophages. CD11c+ dendritic cells supported Th1
responses, whereas CD11b+ macrophages were unable
to do so.
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(Fig. 2E), confirming that IL-12
produced by M. tuberculosis-infected dendritic cells was
actually responsible for polarizing naive T cells to Th1. Together, the
data presented in Figs. 2 and 3 support that microbial stimulation is
sufficient to induce IL-12 production from dendritic cells, which can
then influence naive T cell polarization to the Th1 type. M. tuberculosis selectively suppresses IL-12 production by macrophages
Having shown that M. tuberculosis induces strikingly
different responses from dendritic cells and macrophages with regard to
IL-12 production, we next determined whether M. tuberculosis
was specifically inhibiting the production of IL-12 by macrophages. The
data presented in Fig. 4C show
that if macrophages are stimulated with IFN- and LPS they produce
1.2 ng/ml IL-12p40. However, if the macrophages are pre-exposed to
M. tuberculosis for 6 h before the addition of IFN-
and LPS, IL-12p40 production is significantly suppressed
(p < 0.005). The selectivity of the M.
tuberculosis-induced suppressive effect was tested in parallel
against TNF-. Supernatants of stimulated macrophages with or without
prior exposure to M. tuberculosis had similar levels of
TNF- (Fig. 4D), suggesting that M.
tuberculosis had a selective suppressive effect on IL-12p40
production. M. tuberculosis-infected dendritic cells, in
contrast, did not exhibit a similar significant suppression of IL-12p40
production in response to IFN- and LPS stimuli (Fig. 4A).
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IL-10 is an immunoregulatory cytokine with potent immunosuppressive activity against both APC and Th1 cells (24). IL-10 also potently inhibits the production of several proinflammatory cytokines from macrophages, including IL-12 production (24, 25). IL-12 production by dendritic cells is also down-regulated by IL-10 (26). Recently, IL-10 has been implicated in the generation of regulatory T cells that play a critical role in peripheral tolerance (27). Therefore, we investigated the relationship between IL-10 and IL-12 production in our system.
We first ascertained the levels of IL-10 production by infected
dendritic cells and macrophages. Surprisingly, despite their
Th1-promoting ability, dendritic cells actually secreted significantly
more IL-10 than macrophages (Fig. 5A). We next investigated the
possibility that, although both APC types produce IL-10, it is only
macrophage IL-12p40 production that is sensitive to the
immunosuppressive effects of IL-10. The ability of M.
tuberculosis to induce IL-12 from macrophages derived from IL-10
knockout mice was consequently examined. As shown in Fig. 6, in the absence of endogenous IL-10,
M. tuberculosis-infected macrophages were now fully capable
of making IL-12p70 (Fig. 6A) at levels sufficient to have a
Th1-polarizing effect on naive T cells (Fig. 6B). As
observed above, dendritic cells from wild-type mice made IL-12
following M. tuberculosis infection; nevertheless, in the
absence of IL-10, the levels of IL-12p70 were further enhanced (Fig. 6A). Together, these data indicate that macrophages do not
produce any IL-12 in the presence of IL-10. In addition, the data
indicate that dendritic cell IL-12 production is also sensitive to
inhibition by IL-10 and raise the question of how IL-12 gene is
transcribed in dendritic cells despite the presence of IL-10. One
possible explanation is lack of IL-10R expression on dendritic cells.
However, examination of IL-10R expression on infected dendritic cells
and macrophages revealed that lack of receptor expression is not
responsible for the strong IL-12 production from dendritic cells
despite the presence of IL-10 (Fig. 5B).
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priming synergizes with M. tuberculosis
stimuli to elicit IL-12 production from macrophages
The T cell-derived signals IFN- (28) and CD40
ligand (29) both exert a potent synergistic effect
on IL-12p40 induction in macrophages stimulated with LPS. Therefore, we
tested whether addition of IFN- with M. tuberculosis
would induce IL-12p40 induction from macrophages. Cells were treated
with IFN- and M. tuberculosis, and 24 h later
supernatants were harvested and tested by ELISA for IL-12p40. IL-12p40
protein was secreted by macrophages when stimulated with both M.
tuberculosis and IFN- (Fig. 7).
In addition, there was a conspicuous abrogation of IL-10 production
when macrophages were infected with M. tuberculosis in the
presence of IFN- (Fig. 7). In dendritic cells IFN- treatment
further up-regulated IL-12p40 levels (Fig. 7). These data indicate that
in addition to microbial stimuli, macrophages require a second T
cell-derived signal to elicit IL-12p40 induction. The mechanism
underlying the requirement for a T cell-derived signal appears to be at
the level of IL-10 inhibition.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immature dendritic cells can be modulated to become mature dendritic cells with contrasting phenotypes that can polarize naive T cells in different directions. A subset of mature dendritic cells, for instance, secretes high levels of IL-12 and selectively enhances polarization toward the Th1 phenotype (30). In contrast, an IL-10-secreting dendritic cell subset induces Th2 responses and T cell tolerance (31). Therefore, it was expected that M. tuberculosis-infected dendritic cells that were potent inducers of Th1 responses would secrete high levels of IL-12 and no IL-10, as seen previously with other diverse stimulating conditions (32, 33, 34, 35, 36). Surprisingly, M. tuberculosis-infected dendritic cells secreted both IL-12 and IL-10 but were nevertheless able to initiate Th1 responses from naive T cells. Our data contrast with those demonstrating that IL-10-secreting dendritic cells, in fact, induce immune tolerance (31). We believe that the reason that M. tuberculosis-infected dendritic cells possess Th1-promoting ability may be due to a rapid induction of IL-12 following infection. Once IL-12 is produced, the presence of IL-10 does not have a down-modulating effect on Th1 polarization. This has been reported previously, where exogenous addition of IL-12 biased naive T cells to the Th1 type, and exogenous addition of both IL-12 and IL-10 still resulted in naive T cell differentiation to the Th1 type (37). Future studies will address the kinetics of IL-12 and IL-10 production by dendritic cells and macrophages following M. tuberculosis infection. As previously suggested (38), these data also indicate that dendritic cells do not have an intrinsic attribute for Th1 priming, but have to be environmentally instructed and influenced to acquire Th1 priming capacity.
Contrary to what we observed with dendritic cells, macrophages only
secreted IL-10 with no detectable levels of IL-12 following M.
tuberculosis infection. Because previous studies have shown that
IFN- can synergize with LPS to induce IL-12p40 production from
macrophages, we examined whether IFN- would similarly synergize with
M. tuberculosis to induce IL-12p40 from macrophages. Indeed,
stimulation of macrophages with both IFN- and M.
tuberculosis induced IL-12p40 production, and notably this was
associated with a reciprocal down-regulation of IL-10 production. That
IL-10 is indeed responsible for inhibiting IL-12 production from
macrophages was proved when we observed that macrophages from IL-10
knockout mice were enabled to secrete IL-12 and support Th1 responses.
Interestingly, in the absence of endogenous IL-10, a further
enhancement of IL-12 production occurred in dendritic cells following
infection, suggesting that IL-10 production by dendritic cells
subsequent to IL-12 production may be important for tempering dendritic
cell responses and preventing excessive proinflammatory responses and
ensuing tissue damage.
We speculate that the capacity of dendritic cells, but not macrophages,
to synthesize IL-12 in response to only microbial triggering may have
functional significance for the two APC types during M.
tuberculosis infection. Dendritic cells are present in the
respiratory tract (39) and have been shown to quickly
transport Ag from the airways to the lymph nodes for T cell priming
(40). During this phase of innate immune response it is
important that dendritic cells rapidly make IL-12 in response to
triggering by M. tuberculosis alone. In contrast,
macrophages may have a more important role in the tuberculous
granuloma, where they are in close apposition with activated T cells.
In this microenvironment IFN- secreted by activated T cells can
synergize with M. tuberculosis to down-modulate IL-10
production and allow IL-12 synthesis from macrophages. IFN- at the
same time is able to potentiate antimycobacterial activity of the
macrophages and in addition elevate other macrophage proinflammatory
responses. Subsequently, however, macrophages become refractory to
IFN- signals (41), resulting in down-modulation of
macrophage-induced proinflammatory responses. Thus, the distinct
cytokine response of dendritic cells and macrophages following M.
tuberculosis infection may allow the two cell types to be
effective at different stages of immune response to the pathogen.
Together, these data suggest that macrophages and dendritic cells, albeit both being APC, respond differently following M. tuberculosis infection. Our studies highlight two key differences. First, only M. tuberculosis-infected DCs support Th1 priming because of their unique ability to make IL-12 in response to M. tuberculosis infection, and, second, mechanistically the failure of M. tuberculosis-infected macrophages to synthesize IL-12 is due to IL-10. The fact that dendritic cells are able to synthesize sufficient bioactive IL-12 for Th1 priming despite the production of IL-10 underscores the complexity of the molecular mechanisms regulating IL-12 gene expression in the two APC types. The differences in response of the two types of APCs to M. tuberculosis could be a reflection of their respective roles in immune initiation to M. tuberculosis and granuloma regulation. We promote the concept that dendritic cells capture Ags of M. tuberculosis and transport it to the lymph nodes for T cell priming and Th1 polarization, because they are the primary secretors of IL-12 following M. tuberculosis infection. In contrast, macrophages are important for microbicidal function in the granuloma because they are more efficient in killing intracellular M. tuberculosis (17) and for sustaining Th1 polarity. In summary, the present study strongly positions the IL-12-secreting dendritic cell as the bridge between innate and adaptive immunities in TB, with important implications for dendritic cell-based vaccine design strategies (19, 42).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Padmini Salgame, Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140. E-mail address: salgame{at}astro.temple.edu
3 Abbreviations used in this paper: TB, tuberculosis; MOI, multiplicity of infection; BMM, bone marrow-derived macrophage; BMDC, bone marrow-derived dendritic cell.
Received for publication October 24, 2001. Accepted for publication February 20, 2002.
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