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Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, from T and NK cells (1, 6), as well as enhancing
the cytotoxic activity of these cells (1, 2). However, its
most critical role may be to initiate the development of cell-mediated
immunity by promoting the differentiation of Th1 cells from naive T
cells (7, 8, 9, 10, 11). On the other hand, once a Th1 response is
established, the role of IL-12 has been less clear. Infection of mice with the intracellular protozoan parasite, Leishmania major, has provided a valuable model for the study of Th cell responses, because resistant strains of mice develop a Th1 response and other strains develop nonhealing lesions associated with a Th2 response (12, 13). As predicted, IL-12 is required in the initiation of Th1 cell development in leishmaniasis. In the absence of IL-12, normally resistant strains of mice infected with L. major fail to develop a Th1 response and consequently are unable to control their infections (14, 15, 16, 17). In contrast, susceptible BALB/c mice treated with IL-12 during the first 2 wk of infection (18, 19) or vaccinated with IL-12 and soluble leishmanial Ag (SLA)4 acquire a Th1 phenotype and exhibit resistance to L. major (20).
Once a Th1 response is initiated during an infection, it is believed that IL-12 is not required to sustain the response. For example, administration of anti-IL-12 Abs to mice that had healed from a primary L. major infection did not alter the resistance of these mice on reinfection (21). Similarly, in other infectious diseases, such as Toxoplasma gondii (22) and Listeria monocytogenes (23), maintenance of a protective Th1 response appeared to be IL-12 independent. A major limitation in the interpretation of these experiments is that IL-12 may not have been completely blocked by the neutralizing mAb, and even a small amount of IL-12 could be enough to sustain a Th1 response. Therefore, to conclusively address this issue, L. major-infected IL-12 p40-/- mice (referred to as p40-/- mice in this article) were transiently treated with IL-12 and monitored for maintenance of resistance after cessation of IL-12 treatment. Surprisingly, we observed that despite the development of a Th1 response in p40-/- mice treated with IL-12, the animals were unable to sustain a Th1 response in the absence of IL-12. Thus, in contrast to previous findings, our results indicate that IL-12 is important for both initiation and maintenance of cell-mediated immunity to L. major infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6, BALB/cByJ, and RAG 1-/- C57BL/6 mice, 4–6 wk old, were purchased from The Jackson Laboratory (Bar Harbor, ME). IL-12 p40-/- C57BL/6 mice used in the initial studies were generously provided by Dr. Jeanne Magram (Hoffmann-LaRoche, Nutley, NJ). All subsequent studies as shown in this paper used IL-12 p40-/- mice on the C57BL/6 and BALB/cByJ background, which were purchased from The Jackson Laboratory. Animals were maintained in a specific pathogen-free environment and tested negative to the presence of murine pathogens.
Parasites and Ag
L. major parasites (MHOM/IL/80/Friedlin) were grown in Grace’s insect culture medium (Life Technologies, Gaithersburg, MD) with 20% heat-inactivated FBS (HyClone, Logan, UT), 2 mM glutamine, 100 U/ml penicillin 6-potassium, and 100 µg/ml streptomycin sulfate. Metacyclic promastigote parasites were isolated by negative selection with Arachis hypogae agglutinin as previously described (24). Mice were injected in the hind footpad with 2 x 106 metacyclic parasites. In certain instances, 8 wk after primary infection, mice were inoculated in the contralateral hind footpad with 2 million metacyclic promastigotes. SLA was prepared as previously described (25). To quantitate the number of parasites in the footpad, single-cell suspensions of the lesions were plated in 10-fold serial dilutions in Grace’s insect culture medium starting with a 1:100 dilution. Each sample was plated in triplicate, and the mean of the negative log parasite titer was calculated after 5 days.
In vivo IL-12 treatment
Mice were treated intralesionally with 0.2 µg IL-12 per footpad (Genetics Institute, Cambridge, MA) three times a wk during the first 2 or 4 wk of infection. The course of infection for IL-12-treated and untreated mice was monitored by measuring the footpad sizes with a dial caliper (Starrett, Athol, MA). The lesion size was determined by subtracting the size of the normal hind footpad from the size of the infected hind footpad. In secondary infections, the lesion size was determined by subtracting the size of the hind footpad before challenge from the size of the challenged hind footpad.
In vitro recall responses
Popliteal lymph nodes were harvested, and single-cell
suspensions were prepared. Cells were resuspended at 4 x
106/ml in DMEM, 10% heat-inactivated FBS, 2 mM
glutamine, 100 U/ml penicillin 6-potassium, 100 mg/ml streptomycin
sulfate, 25 mM HEPES, and 5 x 10-5 M 2-ME
and plated at 200 µl/well in 96-well tissue culture plates. Cells
were stimulated with or without 50 µg/ml SLA Ag. In addition, 5
µg/ml anti-IL-4R mAb (M1; a generous gift from Dr. Fred
Finkleman, University of Cincinnati, Cincinnati, OH) was added to block
consumption of IL-4. After 3 days, supernatants were collected and
assayed for IFN- and IL-4 production by ELISA as previously
described (26).
Intracellular cytokine staining
Pooled lymphocytes from the popliteal lymph nodes were
resuspended at 5 x 106/ml and plated at 1
ml in 24-well tissue cultures plates with or without 50 µg/ml SLA.
Intracellular cytokine staining was performed as previously described
with minor modifications (27). Briefly, after 3 days, the
cells were stimulated with 50 ng/ml PMA, 500 ng/ml ionomycin, and 10
µg/ml brefeldin A for 5 h. The cells were washed and incubated
with 10 µg anti-FCIII/IIR Ab (2.4G2) and 10 µg rat IgG
(Sigma, St. Louis, MO) to block nonspecific binding of Abs and then
stained with anti-CD4- or CD8-FITC (PharMingen, San Diego, CA) and
fixed overnight with 1% paraformaldehyde. Cells were then
permeabilized with 0.1% saponin in FACS buffer
(PBS/BSA/Na3) and stained with anti-IFN-
APC and anti-IL-4 PE mAbs or the appropriate isotype controls
(PharMingen). Cells were washed and run on a FACSCalibur cytometer
(Becton Dickinson, San Jose, CA). Analysis was performed with CellQuest
(Becton Dickinson) software.
Adoptive transfer
Draining lymph nodes from C57BL/6 mice that had healed from a L. major infection (6–8 wk postinfection) were collected, and single-cell suspensions were prepared. Cells were incubated with 5 µg/ml anti-CD8 (H35) for 30 min on ice and washed, and rabbit complement (Pel-Freez, Brown Deer, WI) was added at a 1:10 dilution for 1 h at 37°C. The remaining cells were then panned with anti-Ig Abs (Jackson Immunoresearch, West Grove, PA) for 30 min at 37°C to remove B cells. The CD4+-enriched cell population (80–85%) was adoptively transferred by i.v. injection (10 x 106/mouse) into RAG-/-, p40-/-, or wild-type C57BL/6 mice. One day later, the mice were injected with L. major.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 p40-/- C57BL/6
and BALB/c mice were infected with L. major, and some mice
were treated intralesionally with IL-12 six times during a 2-wk period.
As expected, untreated
p40-/- C57BL/6 and BALB/c
mice developed progressive lesions, although the kinetics of lesion
growth was slightly slower in the
p40-/- C57BL/6 mice than
in the BALB/c mice (Fig. 1
). In contrast,
both the IL-12-treated BALB/c and
p40-/- C57BL/6 mice
controlled their lesions for at least the first 7 wk of infection (Fig. 1). The ability to control lesion size correlated with lower parasite
counts in the footpad (Table I). At 2 wk
postinfection, lesions from IL-12-treated
p40-/- mice contained
significantly lower parasite levels compared with those in untreated
p40-/- mice (Table I). We
also observed that at 2 wk postinfection, popliteal lymph node cells
from IL-12-treated p40-/-
mice produced significantly higher levels of IFN- and no detectable
IL-4, unlike cells from control
p40-/- mice which
exhibited a Th2 phenotype (Fig. 2A). At this early time point,
control C57BL/6 mice do not have a pronounced Th1 response in agreement
with previous findings (28).
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production. To examine this, popliteal lymph nodes from 2-wk
IL-12-treated p40-/-,
control p40-/-, and
C57BL/6 mice were harvested. Lymphocytes were stimulated with SLA for 3
days, and then PMA, ionomycin, and brefeldin A were added to the
cultures for 5 h. Cells were then stained for either CD4 or CD8,
as well as intracellular cytokine expression. Consistent with the ELISA
data, IL-12-treated
p40-/- mice displayed
higher IFN- and reduced IL-4 levels than did the untreated
p40-/- mice (Fig. 2
B). Interestingly, the percentage of
CD4+ T cells in the IL-12-treated
p40-/- mice that produced
IFN- was similar to those in C57BL/6 mice (Fig. 2B).
However, only a small percentage (0.5%) of CD8+
T cells of both IL-12-treated
p40-/- and C57BL/6 mice
exhibited IFN- expression (data not shown). We also observed that
the IL-12 treatment did not change the cellular composition of
lymphocytes, which was tested by staining for CD4, CD8, B220, 
TCR, and Mac-1 (data not shown). Thus, IL-12 treatment in the
p40-/- mice promotes
differentiation of CD4+ T cells to the Th1
phenotype. Together, these data indicate that IL-12 treatment was
effective in providing resistance to L. major and initiating
a Th1 response in p40-/-
C57BL/6 mice. Administration of IL-12 to p40-/- C57BL/6 mice fails to induce long term protection
To determine whether the protective immune response exhibited in
IL-12-treated p40-/- mice
would be maintained in the absence of IL-12, we challenged the
IL-12-treated p40-/- mice
8 wk after the primary infection in the contralateral footpad without
administering IL-12. Surprisingly, IL-12-treated
p40-/- mice that had
developed a Th1 response and controlled a primary L. major
infection were unable to control a secondary infection without
exogenous IL-12 administration (Fig. 3).
In addition, on challenge of these IL-12-treated
p40-/- mice, the lesions
at the primary site reemerged (data not shown). In contrast, the
resistance induced by IL-12 treatment in BALB/c mice was maintained on
secondary infection (Fig. 3). Eleven weeks after the secondary
infection, the increased lesion size in the IL-12-treated
p40-/- mice correlated
with a strongly polarized Th2 response, where little IFN- was
detected (Fig. 4). However, challenged
IL-12-treated BALB/c mice produced high IFN- and low IL-4 levels,
which were comparable with that of the healed C57BL/6 mice (Fig. 4).
These data demonstrate that although exogenous IL-12 treatment is
sufficient in protecting BALB/c mice from a primary, as well as a
secondary L. major infection, it is insufficient in
providing long term protection to
p40-/- mice.
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To determine whether longer treatment with IL-12 could induce a
protective response that could be maintained in the absence of IL-12,
we administered IL-12 during the first 4 wk of infection. As before,
IL-12-treated p40-/- mice
were initially able to control the primary infection, unlike the
untreated p40-/- group
(Fig. 5A). Nevertheless, when
challenged at 8 wk, the
p40-/- mice treated with
IL-12 for the first 4 wk of infection were still susceptible to
infection (Fig. 5B), similar to the 2-wk IL-12-treated
p40-/- mice (Fig. 3). As
expected, the increased lesion size was associated with a Th2 response
in the 4-wk IL-12-treated
p40-/- mice (data not
shown). Thus, these results suggest that IL-12 needs to be present
throughout the course of infection to maintain resistance to
L. major.
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Thus, taken together with the studies where mice were rechallenged at 8
wk of infection, these experiments suggest that exogenous IL-12
treatment given to p40-/-
mice induces short term protection but fails to induce long term,
IL-12-independent resistance.
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Because IL-12 treatment can protect BALB/c mice, but not
p40-/- C57BL/6 mice, we
wanted to determine whether endogenous IL-12 could account for the
resistance in BALB/c mice. To address this question, we treated
p40-/- mice on the BALB/c
background with IL-12 during the first 2 wk of L. major
infection and monitored their course of infection. Similar to the
p40-/- C57BL/6 mice,
IL-12 treatment delayed lesion growth but ultimately did not protect
p40-/- BALB/c mice (Fig. 7). Because IL-12 treatment of wild-type
BALB/c, but not p40-/-
BALB/c mice, leads to long term protection, it appears that endogenous
IL-12 is involved in perpetuating the Th1 response in IL-12-treated
BALB/c mice. This fact also extends our results to the BALB/c genetic
background, indicating that the requirement for IL-12 to maintain a Th1
response is not unique to C57BL/6 mice.
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To further investigate the role of IL-12 in maintaining a Th1
response, we asked whether Th1 cells from L. major-infected
C57BL/6 mice would be able to adoptively transfer protection to
p40-/- mice. We
transferred CD4+-enriched T cells from healed
wild-type C57BL/6 mice into
RAG-/-,
p40-/-, and wild-type
C57BL/6 mice. As expected, the CD4+-enriched T
cells exhibited a Th1-type response to SLA in a recall assay, producing
high levels of IFN- and little IL-4 (data not shown). C57BL/6
recipients of Th1 cells exhibited enhanced resistance to L.
major, as indicated by a significant decrease in the number of
parasites within their lesions compared with control C57BL/6 mice
(Table II). In addition, after adoptive
transfer of the Th1 cell population,
RAG-/- recipients were
resistant to L. major infection, whereas control
RAG-/- mice were
susceptible to infection (Fig. 8). As
expected, protection from lesion development was associated with lower
parasite counts. Adoptively transferred
RAG-/- and control
RAG-/- mice contained
103.4 and >109 parasites
within their lesions, respectively (Table II). However, when
CD4+ T cells from healed wild-type mice were
transferred to p40-/-
recipients, they failed to induce any protection to L. major
infection (Fig. 8). Furthermore, the parasite levels in the footpads
were very high in both
p40-/- recipients of Th1
cells and control p40-/-
mice (>109) (Table II). Thus, adoptive transfer
of Th1 cells enhanced parasite clearance in C57BL/6 recipients and
protected RAG-/- mice but
failed to protect p40-/-
mice, further demonstrating that IL-12 is required for established
Th1-committed cells to provide resistance to L. major.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our findings differ from earlier reports which concluded that IL-12 is
not required for continued protection in several infectious diseases
but is essential in the maintenance of autoimmune diseases
(39). We had previously shown that healed C3H mice
reinfected with L. major maintained resistance after
administration of anti-IL-12 Abs (21). Similarly,
others observed that anti-IL-12-treated mice chronically infected
with T. gondii or Listeria monocytogenes survive
and produce IFN- in a manner comparable with that of untreated
controls (22, 23). However, a major caveat in these
studies is that the neutralization of IL-12 may have been incomplete
and low amounts of IL-12 could be sufficient in maintaining Th1 immune
responses. To overcome the technical limitation of these studies, we
examined L. major-infected
p40-/- mice after
cessation of IL-12 treatment and clearly found the requirement for
IL-12 in the maintenance of Th1 responses. Thus, the necessity of IL-12
for the maintenance of a leishmanial-specific Th1 response is similar
to that seen in murine autoimmune models. For example, administration
of blocking Abs to IL-12 given to mice with experimental autoimmune
encephalomyelitis decreased disease severity (36, 37).
Furthermore, in a model of autoimmune uveitis, wild-type cells could
transfer disease to wild-type recipients, but not to
p40-/- mice unless IL-12
was also administered (40). Because the IL-12 dependence
of a Th1 response seen here in experimental leishmaniasis may apply to
other infectious diseases previously thought to be IL-12 independent,
it is possible that no qualitative differences exist for the role of
IL-12 in the maintenance of a Th1 response in infection vs
autoimmunity.
There are several possible explanations as to why IL-12 may be
necessary to maintain an established Th1 response. For example, IL-12
may be required for optimal proliferation of Th cells or for optimal
IFN- production (41, 42). Proliferation and IFN-
production of murine Th1 cell clones are significantly enhanced in the
presence of IL-12 (41). However, several studies using Th1
clones have shown that in the absence of IL-12, Th1 clones are still
capable of producing IFN- (21, 43). Alternatively,
IL-12 could be acting to ensure Th1 cell survival. IL-12 prevents
Fas-mediated apoptosis of Ag-specific T cells (44), and
because Th1 cells have been characterized to be more vulnerable to
Fas-mediated death (45), IL-12 may be especially important
for maintaining Th1 cell survival. Similarly, IL-12 may function as a
tonic survival signal for Th1 cells in the manner that IL-15 has been
shown to maintain CD8+ T cells in vivo
(46). Another intriguing possibility is that IL-12 may be
required to prevent Th2 cell development and replenish the Th1 cell
pool from naive or uncommitted Th0 cells. Despite the ability of
p40-/- mice to initially
make a polarized Th1 response after IL-12 treatment, these mice
developed a Th2 response several weeks after cessation of treatment.
Our observations suggest that IFN- alone is insufficient to suppress
Th2 development and fails to sustain a Th1 response, as seen in other
studies (47, 48). Thus, in the absence of IL-12,
leishmanial-specific naive cells or uncommitted Th0 cells may become
Th2 cells. In fact, Mocci and Coffman (49, 50) have
observed that within a polarized Th1 population from L.
major-infected mice, Mel 14high T cells can
differentiate into either Th1 or Th2 cells. Therefore, IL-12 may be
important in the continuous renewal of Th1 cells from these
undifferentiated precursors. Overall, any one or combination of these
possibilities for how IL-12 is involved in sustaining Th1 responses may
apply, and additional studies will be required to resolve this
issue.
Our finding that IL-12 is an absolute requirement to maintain a Th1 response suggests that the efficacy of vaccines depends on induction and continuous IL-12 production. It may also explain why plasmid IL-12 DNA when used as an adjuvant in an experimental leishmanial vaccine provides longer term protection against L. major than does soluble IL-12 (51). Our data underscore the need to elicit continuous IL-12 production to provide lasting protection against infections requiring cellular immunity.
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Acknowledgments |
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Footnotes |
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2 Current address: Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland, Australia 4029.
3 Address correspondence and reprint requests to Dr. Phillip Scott, Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 216 Rosenthal Building, 3800 Spruce Street, Philadelphia, PA 19104.
4 Abbreviation used in this paper: SLA, soluble leishmanial Ag.
Received for publication March 7, 2000. Accepted for publication April 26, 2000.
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D. Artis, K. Speirs, K. Joyce, M. Goldschmidt, J. Caamano, C. A. Hunter, and P. Scott NF-{kappa}B1 Is Required for Optimal CD4+ Th1 Cell Development and Resistance to Leishmania major J. Immunol., February 15, 2003; 170(4): 1995 - 2003. [Abstract] [Full Text] [PDF]
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A. M. Cleary, W. Tu, A. Enright, T. Giffon, R. Dewaal-Malefyt, K. Gutierrez, and D. B. Lewis Impaired Accumulation and Function of Memory CD4 T Cells in Human IL-12 Receptor {beta}1 Deficiency J. Immunol., January 1, 2003; 170(1): 597 - 603. [Abstract] [Full Text] [PDF]
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G. C. Pien, K. B. Nguyen, L. Malmgaard, A. R. Satoskar, and C. A. Biron A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections J. Immunol., November 15, 2002; 169(10): 5827 - 5837. [Abstract] [Full Text] [PDF]
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Y.-J. Jung, R. LaCourse, L. Ryan, and R. J. North Evidence Inconsistent with a Negative Influence of T Helper 2 Cells on Protection Afforded by a Dominant T Helper 1 Response against Mycobacterium tuberculosis Lung Infection in Mice Infect. Immun., November 1, 2002; 70(11): 6436 - 6443. [Abstract] [Full Text] [PDF]
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F. Aguilar Torrentera, J. D. Laman, M. Van Meurs, L. Adorini, E. Muraille, and Y. Carlier Endogenous Interleukin-12 Is Critical for Controlling the Late but Not the Early Stage of Leishmania mexicana Infection in C57BL/6 Mice Infect. Immun., September 1, 2002; 70(9): 5075 - 5080. [Abstract] [Full Text] [PDF]
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B. John, D. Rajagopal, A. Pashine, S. Rath, A. George, and V. Bal Role of IL-12-Independent and IL-12-Dependent Pathways in Regulating Generation of the IFN-{gamma} Component of T Cell Responses to Salmonella typhimurium J. Immunol., September 1, 2002; 169(5): 2545 - 2552. [Abstract] [Full Text] [PDF]
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A. Y. Park, B. Hondowicz, M. Kopf, and P. Scott The Role of IL-12 in Maintaining Resistance to Leishmania major J. Immunol., June 1, 2002; 168(11): 5771 - 5777. [Abstract] [Full Text] [PDF]
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K. Dabbagh, M. E. Dahl, P. Stepick-Biek, and D. B. Lewis Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4524 - 4530. [Abstract] [Full Text] [PDF]
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A. S. MacDonald and E. J. Pearce Cutting Edge: Polarized Th Cell Response Induction by Transferred Antigen-Pulsed Dendritic Cells Is Dependent on IL-4 or IL-12 Production by Recipient Cells J. Immunol., April 1, 2002; 168(7): 3127 - 3130. [Abstract] [Full Text] [PDF]
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A. M. Cooper, A. Kipnis, J. Turner, J. Magram, J. Ferrante, and I. M. Orme Mice Lacking Bioactive IL-12 Can Generate Protective, Antigen-Specific Cellular Responses to Mycobacterial Infection Only if the IL-12 p40 Subunit Is Present J. Immunol., February 1, 2002; 168(3): 1322 - 1327. [Abstract] [Full Text] [PDF]
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J. E. Uzonna, G. Wei, D. Yurkowski, and P. Bretscher Immune Elimination of Leishmania major in Mice: Implications for Immune Memory, Vaccination, and Reactivation Disease J. Immunol., December 15, 2001; 167(12): 6967 - 6974. [Abstract] [Full Text] [PDF]
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Y. Belkaid, K. F. Hoffmann, S. Mendez, S. Kamhawi, M. C. Udey, T. A. Wynn, and D. L. Sacks The Role of Interleukin (IL)-10 in the Persistence of Leishmania major in the Skin after Healing and the Therapeutic Potential of Anti-IL-10 Receptor Antibody for Sterile Cure J. Exp. Med., November 19, 2001; 194(10): 1497 - 1506. [Abstract] [Full Text] [PDF]
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U. M. Padigel, P. J. Perrin, and J. P. Farrell The Development of a Th1-Type Response and Resistance to Leishmania major Infection in the Absence of CD40-CD40L Costimulation J. Immunol., November 15, 2001; 167(10): 5874 - 5879. [Abstract] [Full Text] [PDF]
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