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Cutting Edge |
Receptors1
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. However, when Ag was
targeted to FcRs on these macrophages, the T cell response was
reversed and biased toward a Th2-like response. This Th2-like phenotype
was stable and was retained when the T cells were subsequently
restimulated under nonbiasing conditions. The T cell biasing and its
reversal via FcR was also observed in vivo. Mice vaccinated with
IgG-opsonized OVA made high levels of IgG Ab of the IgG1 isotype. These
studies demonstrate that the ligation of FcR on activated
macrophages can reverse the Th1 biasing that occurs as a result of
innate immune responses to microbial products. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and provide protection against intracellular
pathogens (2). Th2-like cells produce primarily IL-4,
IL-5, and IL-6, and provide protection against extracellular or
parasitic Ags (3). A number of variables have been shown
to contribute to the deviation of T cells toward either of these
pathways, including the dose of Ag used to induce the immune response
(4), the genetic makeup of the host (5), or
the type of APC that initiates the immune response
(6).
The receptors for the Fc portion of IgG (FcR) allow macrophages to
respond to products of an adaptive immune response. In a series of
independent reports, we have demonstrated that the ligation of specific
FcRs on macrophages can influence the kinetics, quantity, and
character of cytokines produced in response to microbial stimuli
(7, 8, 9). The two cytokines most dramatically modulated by
FcR ligation were IL-12 and IL-10. IL-12 transcription was abrogated
as a consequence of FcR ligation (7, 10), whereas IL-10
transcription was rapidly and dramatically increased (8, 9). These two cytokines are diametrically opposed in their
action. IL-12 is a proinflammatory cytokine that is essential for an
efficient cell-mediated immune response (11). In contrast,
IL-10 can exert potent immunosuppressive activity on macrophages
(12, 13), preventing macrophage activation and diminishing
inflammatory cytokine production. Recent studies have indicated that
activation of innate immunity through Toll-like receptors can influence
the character of the adaptive immune response and preferentially drive
Th1-like T cell differentiation (14).
In this work we used activated macrophages as APCs to determine whether innate immune responses allow these cells to influence T cell responses. These macrophages likely represent the most relevant population of APCs during autoimmune diseases (15), or when complex bacterial Ags are encountered by the host (16), or when Ag is administered in the presence of adjuvants (17). In all of these cases activated macrophages play a central role in presenting Ag to T cells. In this work we show that when activated macrophages encounter Ag they preferentially drive a polarized Th1-like immune response. However, when these APCs encounter immune complexes, their cytokine production is modulated to create a cytokine microenvironment which preferentially induces a Th2-like response predominated by IL-4. Thus IgG, the product of an adaptive immune response, can override innate signals generated by microbial products and drive Th2-like immune responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were purchased from National Cancer
Institute, Charles River Laboratories (Frederick, MD). Breeding
pairs of mice transgenic for OVA323–339, DO11.10
TCR
(18), and IL-12-/- mice
were purchased from The Jackson Laboratory (Bar Harbor, ME). Breeding
pairs of IL-10-/- mice were kindly provided by
D. Rennick (DNAX, Palo Alto, CA). Macrophages were prepared from the
bone marrow progenitors as previously described (10).
CD4+ cells were prepared from the spleens of
DO11.10 mice by immunomagnetic negative depletion (Polysciences,
Warrington, PA). In the primary stimulation, >80% of the T cells were
CD4+CD45RBhigh by flow
cytometry. In the secondary response >95% of the cells were positive
for CD4. For primary stimulation assays, 2 x
105 macrophages were primed overnight with 100
U/ml rIFN- (R&D Systems, Minneapolis, MN). Cells were washed and
stimulated with 10 ng/ml LPS (Escherichia coli 0127:B8;
Sigma-Aldrich, St. Louis, MO) in the presence of 150 µg/ml OVA
(Sigma-Aldrich) or IgG-opsonized OVA (IgG-OVA). IgG-OVA was made by
mixing a 10-fold molar excess of Ab to OVA for 30 min at room
temperature. Following macrophage activation, 5 x
105 CD4+ T cells were added
to each well in a total volume of 0.6 ml of RPMI 1640 (Cellgro,
Herndon, VA) supplemented with 10% FCS, HEPES, sodium pyruvate,
penicillin/streptomycin, and 2-ME. Primary T cell cytokine
measurements were made at 72 h. Seven days following the primary
stimulation, cells were harvested, washed, counted, and added to 3
x 105 fresh macrophages, or in some cases 1
x 105 primary spleen dendritic cells isolated
using CD11c (N418) microbeads (Miltenyi Biotec, Auburn, CA) with 150
µg/ml OVA (secondary stimulation, unbiasing conditions). After
24 h, cytokines were measured by either ELISA or intracellular
staining.
Cytokine measurement
Cytokines were measured by sandwich ELISA using Ab pairs
provided by BD PharMingen (San Diego, CA) (IL-12p70, 9A5 and C17.8;
IL-10, JES-2A5 and JES-16E3; IFN-, R4-6A2 and XMG1.2; IL-4, 11B11
and BVD6–24G2) according to the manufacturer’s instructions.
Intracellular staining was performed on secondarily stimulated T cells
(95% CD4+ by flow cytometry) using BD PharMingen
Cytofix/Cytoperm kit (catalog no. 2076KK) and PE-conjugated Abs
to IL-4 (11B11) or FITC-conjugated Abs to IFN- (R4-6A2). Cells were
analyzed on a FACSCalibur flow cytometer (BD Biosciences, Mountain
View, CA). Quadrants were set to an isotype control Ab for
analysis.
Immunizations
Mice were immunized with either OVA or IgG-OVA in monophosphoryl lipid A (MPL)3 adjuvant (Sigma-Aldrich). Mice were injected i.p. with 100 µg of MPL and 25 µg of Ag in a total volume of 0.25 ml of PBS on days 0 and 10. Serum was collected from all mice on day 21 and an ELISA was performed for Ab measurements. For OVA-specific Ig determinations, plates were incubated with alkaline phosphatase-conjugated goat anti-mouse Ig (H and L chains), IgG1, or IgG2a (Southern Biotechnology Associates, Birmingham, AL). Ab titers were determined as the final dilution of sera that yielded an OD value at 405 nm in excess of 0.1.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Activated macrophages were given OVA in vitro and used to present
Ag to naive CD4+ T cells isolated from
OVA-specific TCR-transgenic mice. Activated macrophages gave rise to a
population of T cells that produced primarily IFN- in the primary
response. After only 3 days of stimulation, T cells exposed to
activated macrophages produced relatively high levels of IFN- but
more modest levels of IL-4 (Fig. 1
A, upper panel).
In contrast, parallel monolayers of activated macrophages pulsed with
OVA opsonized with IgG (IgG-OVA) gave rise to T cells that produced
higher levels of IL-4 and lower levels of IFN- in the primary
response (Fig. 1A, upper panel).
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and low amounts of IL-4 (Fig. 1
A, lower panel). However, when IgG-OVA was used
in the primary response, there was a sustained biasing toward the type
2 phenotype. After secondary stimulation with OVA these T cells
continued to make high levels of IL-4 and lower levels of IFN- (Fig. 1A, lower panel). Similar results were obtained
when T cells were stimulated in the secondary response with Abs to CD3
and CD28 (data not shown).
Flow cytometry to detect intracellular cytokine production by
stimulated T cells was performed after secondary stimulation under
nonbiasing conditions, as described above. A high percentage of T cells
that were stimulated with OVA presented by activated macrophages in the
primary response made IFN- following secondary stimulation (20.5%),
whereas only 2.3% made detectable IL-4 (Fig. 1B, left
panel). In contrast, when T cells were stimulated with macrophages
receiving IgG-OVA in the primary stimulation, only 1.9% of them made
IFN-, whereas 27.2% produced IL-4 in the secondary response (Fig. 1B, right panel).
To further examine the stability of biasing, T cells that were exposed
to macrophages and IgG-OVA in the primary stimulation were restimulated
with a different APC in the secondary stimulation. Primary spleen
dendritic cells were used as the APC to restimulate T cells. Cells that
were stimulated in both the primary and secondary response with OVA
alone produced relatively high levels of IFN- and lower levels of
IL-4 (Fig. 2A). By flow
cytometry 15.8% made IFN- (data not shown). In contrast, cells that
were originally stimulated with IgG-OVA retained their Th2-like
phenotype upon restimulation and produced higher amounts of IL-4 but no
detectable IFN- (Fig. 2A). By flow cytometry, 33.4% of
the CD4+ T cells made IL-4 but only 0.7% made
IFN- (Fig. 2B). Thus, the targeting of Ag to FcR on
activated macrophages promoted the development of a stable Th-2 like
response to that Ag, even when the Ag was subsequently presented by a
different APC.
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One potential explanation for the differences in T cell biasing
that were observed is the possibility that differences in Ag delivery
to the endocytic pathway via the FcR could cause differences in T
cell cytokine production. To eliminate this possibility, equal amounts
of OVA were added to parallel populations of stimulated macrophages.
One population also received erythrocytes opsonized with IgG (E-IgG) to
ligate FcR with an unrelated immune complex. As expected, activated
macrophages receiving OVA alone induced a Th1-like population of T
cells producing high levels of IFN- and little IL-4 upon secondary
stimulation (Fig. 3A). By flow
cytometry 14.7% made IFN- (data not shown). In contrast to
this, macrophages receiving OVA plus E-IgG in the primary stimulation
gave rise to T cells that were of the Th2-like phenotype, making
primarily IL-4 and little IFN- (Fig. 3A). Approximately
one-third of the T cells in this population stained positively for
IL-4, whereas <5% were positive for IFN- (Fig. 3B). The
biasing observed in response to OVA plus E-IgG was equivalent in
character to that observed when macrophages were given IgG-OVA (compare
Figs. 3B and 1B).
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Cytokine production by macrophages was analyzed and correlated
with subsequent T cell development to determine whether innate
activation of these cells influenced T cell biasing. Activated
macrophages exposed to OVA Ag produced relatively high levels of IL-12
but only modest levels of IL-10 (Fig. 4A, left panel).
This observation is consistent with our previous reports of cytokine
production by macrophages stimulated by a variety of microbial products
(10, 11). Parallel wells of macrophages were stimulated in
the same way but were given IgG-OVA as the Ag instead of OVA alone. The
cytokine profile of these macrophages was dramatically altered (Fig. 4A, left panel). Following FcR ligation by
IgG-OVA, IL-12 production decreased to undetectable levels and IL-10
levels were dramatically increased, as previously described using
insoluble immune complexes (12). As described in Fig. 1, wild-type macrophages receiving OVA alone gave rise to Th1-like T
cells, whereas macrophages receiving IgG-OVA gave rise to Th2-like T
cells (Fig. 4A, right panel). To show that the
biasing that occurred in response to IgG-OVA was due to alterations in
macrophage cytokine production, similar studies were performed on
parallel populations of T cells, using macrophages from gene knockout
mice lacking either IL-12 or IL-10. The stimulation of macrophages from
IL-12-/- mice with LPS failed to induce the
production of IL-12, as expected (Fig. 4B, left
panel); therefore, these macrophages failed to induce a Th1-like
polarized T cell response to OVA (Fig. 4B, right
panel). Instead these macrophages gave rise to a Th0-like
population of T cells that made both IFN- and IL-4 (Fig. 4B, right panel). The IL-4 levels produced by T
cells encountering IL-12-/- macrophages was
significantly higher than those observed with wild-type macrophages
(compare A and B in Fig. 4). These
IL-12-/- macrophages made normal levels of
IL-10 in response to IgG-OVA (Fig. 4B, left
panel); therefore, they were fully capable of biasing toward the
Th2-like phenotype (Fig. 4B, right panel).
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C, left panel). As a
result, these macrophages failed to give rise to Th2-like T cells when
stimulated with IgG-OVA (Fig. 4C, right panel).
There was substantial production of IFN- and minimal IL-4 produced
by T cells in response to IgG-OVA. Both of these parameters were
significantly different from stimulation by wild-type macrophages
(compare C to A in Fig. 4). These activated
IL-10-/- macrophages made normal levels of
IL-12 (Fig. 4C, left panel); therefore, they were
fully capable of inducing Th1-like responses to OVA alone (Fig. 4C, right panel). Thus, both APC-derived
cytokines, IL-10 and IL-12, are involved in T cell biasing. Biasing the immune response in vivo
An in vivo experiment was performed to determine the extent to
which the biasing we observed in vitro could affect immune responses in
whole animals. DO11.10 mice were immunized with OVA or IgG-OVA in MPL
as an adjuvant. This adjuvant was chosen because of its low toxicity
and its potential for use in human vaccines (19). Mice
that were immunized with IgG-OVA made significantly higher total
levels of OVA-specific IgG Ab, as well as IgG1, compared with mice that
were immunized with OVA alone (Fig. 5).
There was no significant increase in either IgM (data not shown) or
IgG2a (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rs on activated macrophages
can reverse innate Th1-like biasing and result in the production of
Ag-specific T cells that preferentially produce Th2-like cytokines.
Activated macrophages were used in these studies as APCs. These cells
have been shown to be relevant APCs in a number of autoimmune diseases,
including arthritis, multiple sclerosis, and diabetes
(20). These activated macrophages produced high levels of
proinflammatory cytokines and preferentially gave rise to T cells that
produced high levels of IFN- in both the primary and secondary
response. We show that the ligation of FcR on activated macrophages
can reverse the Th1-like biasing and drive a Th2-like response instead.
This biasing in T cell cytokine production was dramatic and rapid,
being observed after only 3 days of primary exposure to Ag in vitro and
persisting during secondary stimulation under a variety of nonbiasing
conditions. Importantly, Th2 biasing following FcR ligation was not
due to alterations in the targeting of Ag to the endocytic pathway,
because FcR ligation with an irrelevant immune complex, E-IgG,
reversed innate biasing as well as did IgG-OVA.
To demonstrate that the biasing was due to macrophage cytokines, a
series of studies was performed with macrophages from knockout mice.
Activated macrophages from mice lacking IL-12 failed to bias toward a
Th1-like response. Conversely, macrophages from mice lacking IL-10
failed to induce a Th2-like response following FcR ligation. Thus,
both macrophage-derived cytokines influence T cell biasing. In vivo
studies were performed to measure Ab production in mice immunized with
either OVA or IgG-OVA. Mice immunized with IgG-OVA made more total IgG
Ab than those receiving OVA alone, and a substantial portion of the Ig
was of the IgG1 isotype, indicative of a Th2 response. This is similar
to the recent observation by Heyman et al. (21) that
IgG-TNP complexes induced a Th2 response in mice.
These studies may influence vaccine development, where a strategy to
exploit the Th2-potentiating effects of macrophage FcR ligation may
affect the class and abundance of Ab that is produced. The use of
adjuvants during vaccination is likely to induce a population of APCs
that are similar to the macrophages that were used in this study. This
work may also apply to infectious diseases where inappropriate Th2-like
responses to intracellular pathogens have been shown to occur in the
presence of high levels of host IgG (22, 23). Finally,
these studies are likely to pertain to autoimmunity where Th1 responses
are associated with disease progression (20). In many of
these diseases, activated macrophages similar to the ones used in the
present study have been shown to be important APCs.
In this work, we show that the phenotype of an activated macrophage can
be dramatically changed simply by ligating the FcRs. We show that
this ligation can modify the very character of the immune response that
develops. Similar studies to determine whether other APCs behave
similarly are under way. The present observations are somewhat
enigmatic given the wealth of clinical experience showing that, in many
settings, immune complexes are associated with both acute and chronic
inflammation. The roles for Ab and/or complement in these diseases are
undoubtedly complex. The challenge will be to define the appropriate
settings and the cell types that will allow us to exploit the present
information to reliably deviate immune responses in the desired
direction.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David M. Mosser, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742. E-mail address: dm268{at}umail.umd.edu
3 Abbreviations used in this paper: MPL, monophosphoryl lipid A.
Received for publication January 11, 2002. Accepted for publication February 14, 2002.
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References |
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-chemokines rather than IL-12. J. Immunol. 165:4388.RI. J. Exp. Med. 188:217. receptors. J. Immunol. 166:6861. receptor ligation. J. Immunol. 166:4498.This article has been cited by other articles:
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H. Xiong, H. Li, Y. Chen, J. Zhao, and J. C. Unkeless Interaction of TRAF6 with MAST205 Regulates NF-{kappa}B Activation and MAST205 Stability J. Biol. Chem., October 15, 2004; 279(42): 43675 - 43683. [Abstract] [Full Text] [PDF]
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P. A. Darrah, M. C. G. Monaco, S. Jain, M. K. Hondalus, D. T. Golenbock, and D. M. Mosser Innate Immune Responses to Rhodococcus equi J. Immunol., August 1, 2004; 173(3): 1914 - 1924. [Abstract] [Full Text] [PDF]
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C. F. Anderson, M. Lucas, L. Gutierrez-Kobeh, A. E. Field, and D. M. Mosser T Cell Biasing by Activated Dendritic Cells J. Immunol., July 15, 2004; 173(2): 955 - 961. [Abstract] [Full Text] [PDF]
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T R D J Radstake, P L E M van Lent, G J Pesman, A B Blom, F G J Sweep, J Ronnelid, G J Adema, P Barrera, and W B van den Berg High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon Fc{gamma}R triggering Ann Rheum Dis, June 1, 2004; 63(6): 696 - 702. [Abstract] [Full Text]
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H. Zhou, H. Xiong, H. Li, S. E. Plevy, P. D. Walden, M. Sassaroli, G. D. Prestwich, and J. C. Unkeless Microtubule-Associated Serine/Threonine Kinase-205 kDa and Fc{gamma} Receptor Control IL-12 p40 Synthesis and NF-{kappa}B Activation J. Immunol., February 15, 2004; 172(4): 2559 - 2568. [Abstract] [Full Text] [PDF]
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T. Katakura, M. Miyazaki, M. Kobayashi, D. N. Herndon, and F. Suzuki CCL17 and IL-10 as Effectors That Enable Alternatively Activated Macrophages to Inhibit the Generation of Classically Activated Macrophages J. Immunol., February 1, 2004; 172(3): 1407 - 1413. [Abstract] [Full Text] [PDF]
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K. C. Dowdell, D. J. Cua, E. Kirkman, and S. A. Stohlman NK Cells Regulate CD4 Responses Prior to Antigen Encounter J. Immunol., July 1, 2003; 171(1): 234 - 239. [Abstract] [Full Text] [PDF]
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 F. Bard, R. Barbour, C. Cannon, R. Carretto, M. Fox, D. Games, T. Guido, K. Hoenow, K. Hu, K. Johnson-Wood, et al. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology PNAS, February 18, 2003; 100(4): 2023 - 2028. [Abstract] [Full Text] [PDF]
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D. M. Mosser The many faces of macrophage activation J. Leukoc. Biol., February 1, 2003; 73(2): 209 - 212. [Full Text] [PDF]
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C. Sedlik, D. Orbach, P. Veron, E. Schweighoffer, F. Colucci, R. Gamberale, A. Ioan-Facsinay, S. Verbeek, P. Ricciardi-Castagnoli, C. Bonnerot, et al. A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation J. Immunol., January 15, 2003; 170(2): 846 - 852. [Abstract] [Full Text] [PDF]
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 C. F. Anderson, J. S. Gerber, and D. M. Mosser Modulating macrophage function with IgG immune complexes Innate Immunity, December 1, 2002; 8(6): 477 - 481. [Abstract] [PDF]
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F. P. Polack, M. N. Teng, P. L.Collins, G. A. Prince, M. Exner, H. Regele, D. D. Lirman, R. Rabold, S. J. Hoffman, C. L. Karp, et al. A Role for Immune Complexes in Enhanced Respiratory Syncytial Virus Disease J. Exp. Med., September 16, 2002; 196(6): 859 - 865. [Abstract] [Full Text] [PDF]
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G. J. Randolph, G. Sanchez-Schmitz, R. M. Liebman, and K. Schakel The CD16+ (Fc{gamma}RIII+) Subset of Human Monocytes Preferentially Becomes Migratory Dendritic Cells in a Model Tissue Setting J. Exp. Med., August 19, 2002; 196(4): 517 - 527. [Abstract] [Full Text] [PDF]
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C. F. Anderson and D. M. Mosser A novel phenotype for an activated macrophage: the type 2 activated macrophage J. Leukoc. Biol., July 1, 2002; 72(1): 101 - 106. [Abstract] [Full Text] [PDF]
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