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* Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Environmental Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, the critical role for IL-12
in maintaining cell-mediated immunity may be to prevent the loss of Th1
cells during a challenge infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results raise the question of what role IL-12 plays once
cell-mediated immunity is established. Although IL-12 is best known for
initiating the development of a Th1 response, there are other
activities that might contribute to the maintenance of a Th1 response.
IL-12 promotes cell division and inhibits apoptosis of T cells
expressing a functional IL-12R, thus promoting the expansion of a Th1
response (14, 15, 16, 17, 18, 19, 20). IL-12 can also block Th2 responses, as
seen in L. major-infected BALB/c mice treated with IL-12
(21, 22). Thus, IL-12 may be required to inhibit the
development of Th2 cells, which uncontrolled might overwhelm the
established Th1 response. Finally, IL-12 directly augments the effector
function of established Th1 cells by promoting IFN- synthesis
following cell activation (15), and thus, although Th1
cells might be present, their functional capacity may be limited.
In this study, we investigated the mechanisms that might be involved in the requirement for IL-12 to maintain cell-mediated immunity once it is established. Our first experiments confirmed that IL-12, and not IL-23, was required to maintain a Th1 response following infection with L. major. Next, we found that the loss of a Th1 response and susceptibility to L. major in IL-12-deficient mice was not due to the action of IL-4 in promoting a nonprotective Th2 cell population, because IL-12 and IL-4 doubly deficient mice exhibited the same phenotype as IL-12-deficient mice. Finally, we followed the fate of a Th1 cell population in IL-12-deficient mice and discovered that in the absence of IL-12, Th1 cells are eliminated during an infection, suggesting that IL-12 has a direct role in the ability to maintain a Th1 cell population.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 (B6), B6 IL-12 p40-/-, B6 IL-12 p35-/-, B6 Thy-1.1 congenics, BALB/c, BALB/c p40-/-, and BALB/c DO11.10 TCR transgenic mice were purchased from The Jackson Laboratory (Bar Harbor, ME). IL-12 p35 x IL-4 doubly deficient (p35,IL-4-/-) B6 mice and IL-4-/- B6 mice were generated by M. Kopf and generously provided by E. Pearce (University of Pennsylvania, Philadelphia, PA). The p35,IL-4-/- mice were found to be susceptible to L. major (F. Mattner and M. Kopf, unpublished data). Animals were used at 4–6 wk of age and were maintained in a specific pathogen-free environment and tested negative for 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, Grand Island, NY) with 20% heat-inactivated FBS (HyClone Laboratories, 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 (23). Mice were injected in the left hind footpad with 2 x 106 metacyclic parasites. After 8 wk postprimary infection, mice were inoculated in the contralateral hind footpad with 2 x 106 metacyclic promastigotes. Soluble leishmanial Ag (SLA)3 was prepared as previously described (24).
In vivo IL-12 treatment
Mice were treated intralesionally with 0.2 µg IL-12 per footpad (Genetics Institute, Cambridge, MA) three times per week over the first 2 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 comparing the size of the footpad before and after challenge.
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 flat-bottom 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 F.
Finkelman, University of Cincinnati, Cincinnati, OH, and Immunex,
Seattle, WA) was added to block consumption of IL-4. In some instances,
1 ng/ml IL-12 was added in vitro. Three days later, supernatants were
collected and assayed for IFN- and IL-4 production by ELISA, as
previously described (25).
Adoptive transfers
Single cell suspensions were prepared from the spleen and/or
draining lymph nodes of donor mice, which included C57BL/6
Thy-1.1+ mice that had healed a primary infection
with L. major (
6 wk postinfection) and BALB/c D011.10 TCR
transgenic mice. Cells were incubated with 5 µg/ml anti-CD8
(H35-17.2; IgG2b; hybridoma generously provided by J. P. Farrell,
University of Pennsylvania) 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 Laboratories, West Grove, PA)
for 30 min at 37°C to remove B cells. The
CD4+-enriched cell populations (80–85%) were
adoptively transferred by i.v. injection (10 x
106/mouse) into a variety of recipient mice. As
indicated in the figure legends, in some experiments the recipients
were adult thymectomized, lightly irradiated (400 rad), and/or treated
on days -1, 0, 7, and 14 with 1 mg injection of anti-Thy-1.2 mAb
(30H12; IgG2b; purified from ascites and tested endotoxin free;
hybridoma generously provided by M. Greene and G. Massey, University of
Pennsylvania). For some experiments, cells from
Thy-1.1+ C57BL/6 mice that had healed a primary
infection with L. major were cultured with SLA under Th1
cell-promoting conditions (1 ng/ml IL-12 and 10 µg/ml anti-IL-4
mAb (11B11)) to expand Ag-specific cells. After 3 days in culture,
lymphocytes were enriched for CD4+, as described
above, and used for cell transfer. Similarly, D011.10 lymphocytes from
lymph nodes and spleens were cultured with 1 ng/ml OVA peptide
(323–339) under Th1 cell-promoting conditions (1 ng/ml IL-12 and 10
µg/anti-IL-4 mAb (11B11)). OVA peptide (323–339) was synthesized
by the Protein Chemistry Laboratory, University of Pennsylvania. After
4 days, cells were washed thoroughly in PBS and enriched for
CD4+ T cells, as described above. Some of the
cells were incubated with 10 µg anti-FCIII/IIR Ab (2.4G2) and
10 µg rat IgG (Sigma-Aldrich, St. Louis, MO) to block nonspecific
binding of Abs, and stained with KJ126-FITC (Caltag Laboratories,
Burlingame, CA) and anti-CD4 PE (BD PharMingen, San Diego, CA).
Based on the FACS profile, 10 x 106
clonotypic
KJ-126+CD4+ cells
from naive D011.10 mice or Th1 cells were used for cell transfer.
Detection and intracellular cytokine staining of TCR transgenic T cells
Lymphocytes were pooled from the lymph nodes and spleens of
IL-12 p40-/- or wild-type BALB/c recipients and
stained for KJ-126 and CD4, as described above. The number of D011.10 T
cells present in the recipients was determined by multiplying the total
number of viable cells recovered by the percentage of
CD4+, KJ-126+ events
obtained by flow cytometry. The remaining cells were resuspended at
5 x 106/ml and plated at 1 ml in 24-well
tissue cultures plates with or without 1 ng/ml OVA
peptide323–339. A total of 10 µg/ml
anti-IL-12 mAb (C17.8) was added to all of the wells. After 24
h, surface staining for KJ-126 and CD4 and intracellular cytokine
staining for IFN- were performed, as previously described
(26).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-12 is a heterodimer composed of a p40 and p35 subunit, both of
which are required for IL-12 function. Infection of mice that lack
either of these subunits of IL-12 leads to extreme susceptibility to
infection, associated with a Th2 response (27). In
previous studies, we found that the susceptibility of
p40-/- mice to L. major was
temporarily reversed by administration of IL-12, and control of the
parasites was associated with the development of a Th1 response
(11). However, upon rechallenge in the absence of IL-12,
p40-/- mice were found to be susceptible.
Recently, a new cytokine, called IL-23, has been discovered that uses
the p40 chain of IL-12 in combination with a unique subunit, p19
(28). IL-23 has been implicated in enhancing proliferation
and IFN- production of memory T cells (28), and
therefore we were interested to know whether IL-23, instead of IL-12,
might be the required cytokine to maintain resistance to L.
major. Because p40-/- mice will lack the
activity of both IL-12 and IL-23, while p35-/-
mice will only lack the activity of IL-12, we compared the ability of
these two IL-12-deficient mouse strains to maintain resistance to
L. major after transient treatment with IL-12. Mice were
infected with L. major and some groups treated with IL-12
for the first 2 wk of infection. For at least the first 8 wk of
infection, transient IL-12 treatment was associated with control of
leishmaniasis in both p40-/- and
p35-/- mice (Fig. 1
A). In contrast,
IL-12-deficient mice not treated with IL-12 developed uncontrolled
lesions, and had to be sacrificed by 6 wk of infection. We then
challenged the groups of mice that had been transiently treated with
IL-12 during the primary infection, but without any additional
administration of IL-12. As we previously reported,
p40-/- mice were unable to maintain their
resistance when challenged (11). In addition,
p35-/- mice were also unable to maintain
resistance to L. major (Fig. 1B). Although the
lesions were slightly smaller in the p35-/-
mice compared with the p40-/- mice, in a second
experiment no difference was observed between
p35-/- and p40-/-
animals. These results do not preclude a role for IL-23 in resistance,
because the requirement for IL-12 might mask any protective
contribution of IL-23. However, they do confirm the absolute dependence
upon IL-12 for mice to maintain resistance to L. major.
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The reason IL-12 is required to maintain an established Th1
response is unknown. One possibility is that IL-12 is continuously
required to prevent Th2 cell development during an established Th1
response. Therefore, to determine whether blocking the capacity to
develop a Th2 response would eliminate the requirement for IL-12, we
infected p35,IL-4-/- mice with L.
major and treated the animals with IL-12 for the first 2 wk of
infection to induce a Th1 response (Fig. 2). When Ag-specific responses were
assessed 2 wk after infection, cells from
p35-/- and p35,IL-4-/-
mice that had been treated with IL-12 produced substantial levels of
IFN-, but little IL-13 (Fig. 3, A and B), indicating that the exogenous IL-12 was
effective at inducing a Th1 response in mice lacking IL-12. This Th1
response was associated with substantial control of the L.
major infection, as is evident in Fig. 2A.
Nevertheless, upon reinfection, the p35,IL-4-/-
mice that had been transiently treated with IL-12 in the primary
infection were unable to control L. major and developed
progressive infections, although more slowly than
p35-/- mice (Fig. 2B). An analysis
of the immune response in IL-12-deficient mice indicated a complete
loss of the Th1 response in both p35-/- and
p35,IL-4-/- animals (Fig. 3C).
Interestingly, only in the p35-/- mice was
there a compensatory increase in a Th2 response, as measured by IL-13
production (Fig. 3D). Taken together, these results strongly
suggest that while a Th2 response may promote more rapid lesion
development, the inability to maintain a Th1 response in the absence of
IL-12 is not solely due to the development of a compensatory Th2
response.
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To determine whether the inability of Th1 cells to provide
protection to L. major in the absence of IL-12 is due to the
loss of Th1 cells, we transferred Thy-1.1+
CD4+ T cells from healed C57BL/6 mice into
p40-/- (Thy-1.2+) and
wild-type mice (Thy-1.2+) that were immediately
infected. One group of recipients (Thy-1.2) was depleted of endogenous
T cells by adult thymectomy and treatment with anti-Thy-1.2 mAb,
while another group was untreated. A comparison of the course of
infection in p40-/- mice that were or were not
depleted of endogenous T cells indicated that Th1 cells were slightly
more effective in controlling infection in T cell-depleted recipients
(Fig. 4, A and B).
Nevertheless, all of the p40-/- mice that had
received CD4+ T cells from healed mice developed
an uncontrolled infection. After 6 wk, the recipient mice were
sacrificed, the draining lymph nodes were harvested, and cells were
sorted into Thy-1.1+ (donor) and
Thy-1.2+ (recipient) cells. Similar numbers of
donor cells were recovered from p40-/- and
wild-type mice. The cells were then stimulated with SLA, with or
without the addition of IL-12, and the production of IFN- and IL-4
was assessed. As seen in Fig. 4C, donor cells
(Thy-1.1+) from wild-type (C57BL/6) recipients
produced IFN- upon stimulation with SLA. In contrast, donor cells
harvested from p40-/- recipients failed to
produce IFN- in response to SLA. Because IL-12 augments IFN-
production, it was possible that Th1 cells were present, but failed to
make IFN- due to the absence of IL-12. This possibility does not
seem likely, because even with the addition of IL-12 in vitro, donor
cells taken from p40-/- mice still failed to
produce IFN- (Fig. 4C). In contrast, donor cells from
p40-/- mice produced substantial levels of IL-4
after Ag stimulation (Fig. 4D). Thus, although the recovery
of donor cells was similar in wild-type and IL-12-deficient mice, there
appeared to be a specific loss of leishmanial-specific Th1 cells in
p40-/- mice.
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To determine whether the loss of Th1 cells in IL-12-deficient mice
occurred independently of Ag stimulation, we compared the recovery of
Th1 cells after transfer into wild-type or
p40-/- mice that were not infected with
L. major. These experiments were performed as described
above, except the recipient mice were not challenged. Thus, a Th1
population from healed Thy-1.1+ C57BL/6 mice was
transferred into either Thy-1.2+ wild-type or
p40-/- mice. After 4 wk, mice were sacrificed,
and the survival of the Th1 cells was assessed.
CD4+ Thy-1.1+ T cells were
detected in uninfected wild-type and p40-/-
recipients at similar numbers (Fig. 5A). To test whether these
recovered Thy-1.1+ CD4+
maintained a Th1 phenotype, we stimulated the cells with SLA and
measured the production of IFN- (Fig. 5B). In contrast to
our results with infected mice, we observed similar levels of IFN-
produced by both wild-type and p40-/-
recipients (Fig. 5B). Thus, in the absence of Ag, Th1 cells
do not appear to require IL-12 to be maintained in vivo.
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A) and frequency (Fig. 6B) of Ag-specific DO11.10 CD4+ Th1
cells recovered were similar between BALB/c and
p40-/- BALB/c mice. In agreement with previous
reports using wild-type recipients for transfer of naive DO11.10 T
cells (29), naive CD4+ T cells were
recovered in substantially reduced frequency compared with the recovery
of the Ag-experienced Th1 population. When we tested for the percentage
of IFN--producing cells, the numbers were similar in both wild-type
and p40-/- recipients, as assessed by
intracellular cytokine staining (Fig. 6C). As expected, the
cells that were previously polarized to a Th1 cell population contained
significantly more IFN--positive cells than the donor naive DO11.10
T cells. From these results, we conclude that in the absence of
stimulation, Th1 cells are not dependent upon IL-12 to be maintained
in vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, or
to their deletion during infection. By using Thy-1 disparate mice, we
were able to show that the lack of a Th1 response in IL-12-deficient
mice is associated with a loss of the Th1 cells. Although IL-12 can
enhance IFN- production by Th1 cells, these results suggest that
IL-12 is required for more than optimizing IFN- levels. We also
considered that IL-12 may be required to inhibit the development of a
Th2 response. However, even in mice that lack IL-4 and any evidence of
a concomitant Th2 response, IL-12 was required for maintaining
resistance. Similarly, we considered the possibility that IL-12 might
function as a homeostatic survival factor for
CD4+ Th1 cells, much the way IL-15 has been
reported to maintain CD8 T cells (30). However, we found
that IL-12 was not required to maintain Th1 cells in the absence of Ag
stimulation. Thus, the requirement for IL-12 is only evident during an
ongoing T cell response. Taken together, these results suggest that
IL-12 maintains resistance by keeping a population of Th1 effector
cells present in infected mice.
The role of IL-12 in maintaining a Th1 effector cell population might
best be understood in the context of how memory
CD4+ T cells function. One memory T cell model
suggests the existence of two memory T cell subsets
(31, 32, 33, 34, 35, 36, 37, 38, 39); one subset has the characteristics of effector
cells, while the other subset acts as a reservoir of Ag-specific T
cells that have not committed to a specific cytokine profile, and hence
are referred to as nonpolarized (Tnp). These cells are able to renew
the effector T cell pool as required. The Tnp subset, termed T central
memory cells (32), expresses the chemokine receptor CCR7
and the adhesion molecule CD62L (L-selectin), which target the cells to
the lymph nodes. The other subset, termed T effector memory cells,
produces effector cytokines (such as IFN- or IL-4) and migrates
through the tissues. The existence of CD4+ memory
T cells with the characteristics of Tnp (or T central memory cells) and
T effector memory cells now seems well established (15, 37, 40, 41). Particularly relevant, we and others have demonstrated that
L. major-infected C3H and B6 mice contained
CD4+ CD62L high T cells that were Ag reactive and
capable of becoming either Th1 or Th2 cells depending upon the culture
conditions, analogous to Tnp cells, and were also able to show the
nonpolarized nature of similar T cells from L.
major-infected mice in adoptive transfer experiments (34, 35, 42).
The existence of a Tnp population that acts as a reservoir of Ag-reactive T cells capable of becoming Th1 effector cells provides a logical role for IL-12 in maintaining immunity. We propose that IL-12 is required to promote the development of Th1 effectors from the Tnp population. Our studies demonstrated that after CD4 T cells from healed mice (tracked by differential expression of the T cell marker, Thy-1) were transferred to wild-type C57BL/6 L. major-infected mice, a Th1 response by the donor cells was evident several weeks later. In contrast, we were unable to recover a Th1 response by the same T cell population when transferred to L. major-infected IL-12p40-deficient mice. The T cell population transferred in this experiment would have contained Tnp and Th1 cells (and probably naive T cells) that were Leishmania specific. We hypothesize that the Th1 cells recovered from the wild-type mice 6 wk after infection were daughter cells of Tnp cells that had differentiated during infection, and that most of the original donor Th1 cells were deleted by activation-induced cell death. In IL-12-deficient mice, the Tnp cells would be unable to differentiate into Th1 cells, thus leading to a loss of a Th1 response. Consistent with this hypothesis was our finding that there was no difference in the recovery of Th1 cells in wild-type and IL-12-deficient mice if they were not challenged, possibly because the Th1 cells were better able to survive in the absence of activation.
Another possibility, which is not mutually exclusive with a role for IL-12 in promoting the development of Th1 cells from Tnp cells, is a role in preventing T cell apoptosis. Previous studies indicate that IL-12 prevents apoptosis of Ag-specific T cells (17, 18, 19), and because Th1 cells have been characterized to be more susceptible than Th2 cells to Fas-mediated apoptosis (43), IL-12 may be important in Th1 cell survival during an ongoing cell-mediated immune response. Indeed, it is possible that in the absence of IL-12, Th1 cells may be particularly prone to cell death, which would lead to a greater need for Tnp cells to differentiate into Th1 effector cells, a pathway that would be blocked in the absence of IL-12. Finally, IL-12 might be required to expand the Th1 cell population, and in this regard it was recently found that proliferation of autoreactive T cells is deficient in the absence of IL-12 (20).
The studies examining the role of IL-12 in maintaining immunity have
been performed using either anti-IL-12 p40 mAb or
p40-/- mice. In addition to p35, p40 pairs with
another subunit, p19, to form IL-23 (28). The importance
of IL-23 in the development and maintenance of cell-mediated immunity
has yet to be fully characterized. Clearly, IL-23 is not sufficient in
inducing early Th1 cell development during L. major
infection, because p35-/- mice, which have
intact IL-23, still remain susceptible (shown in this work and in Ref.
27). However, IL-23 has been shown to induce proliferation
of mouse memory CD4+
CD45RBlow T cells and IFN- production of human
memory T cells (28). Because
p40-/- mice lack both IL-12 and IL-23, it was
possible that the absence of IL-23 was responsible for the loss of
immunity in the IL-12-treated p40-/- mice.
However, both p40-/- and
p35-/- mice treated with IL-12 were equally
unable to maintain a Th1 cell response. Because we did not examine the
role of IL-23 in our adoptive transfer studies, it is possible that
IL-23 contributes to memory T cell activation, but our data clearly
indicate that by itself it is insufficient to maintain protection in
IL-12-treated p35-/- mice.
Our observation that p35,IL-4-/- C57BL/6 mice
were unable to control L. major infection is an interesting
finding, because previous results show that simultaneous treatment with
anti-IL-12 and anti-IL-4 mAbs prevents disease progression in
L. major-infected C57BL/6 mice (44). The
discrepancy between these results is most likely due to the inability
to neutralize all of the endogenous IL-12 using mAbs. Our results with
p35,IL-4-/- mice underscore the central role
IL-12 plays in resistance to L. major. Resistance to several
bacterial and viral infections can be IL-12-independent, although
IFN--dependent (45, 46, 47, 48, 49, 50, 51). It was conceivable that in the
absence of an IL-4-mediated Th2 response, sufficient IFN- might be
produced by IL-12-independent mechanisms to promote resistance.
However, this was not the case. Whether IL-10 is involved in promoting
disease progression in p35,IL-4-/- mice, as
IL-10-/- mice exhibit greater control over the
infection (52, 53), has yet to be determined.
It is likely that IL-12 will be required to maintain cell-mediated
immunity to other pathogens, although the types of studies described in
this work and previously have only been done with L. major
and Toxoplasma gondii (11, 12, 13). The practical
component to these observations is that modulation of IL-12 levels may
be important for altering immunopathologic responses associated with
certain infectious diseases, in the same way that interventions have
been developed for autoimmune diseases. Moreover, they suggest that the
efficacy of vaccines will depend on the induction and continuous
production of IL-12, or at least the production of IL-12 at the time of
challenge, which may explain why plasmid IL-12 DNA provides better
protection when used in a leishmanial vaccine than IL-12 protein
(54). Our results indicate that rather than modulating the
development of a Th2 response, or optimizing IFN- production by Th1
cells, the critical role of IL-12 may be to ensure that Th1 cells are
not eliminated during a challenge infection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Phillip Scott, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104. E-mail address: pscott{at}vet.upenn.edu
3 Abbreviations used in this paper: SLA, soluble leishmanial Ag; Tnp, nonpolarized T cell.
Received for publication January 28, 2002. Accepted for publication March 25, 2002.
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U. M. Padigel, N. Kim, Y. Choi, and J. P. Farrell TRANCE-RANK Costimulation is Required for IL-12 Production and the Initiation of a Th1-Type Response to Leishmania major Infection in CD40L-Deficient Mice J. Immunol., November 15, 2003; 171(10): 5437 - 5441. [Abstract] [Full Text] [PDF]
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L. G. Bermudez-Humaran, P. Langella, N. G. Cortes-Perez, A. Gruss, R. S. Tamez-Guerra, S. C. Oliveira, O. S. Cardenas, R. Montes de Oca-Luna, and Y. Le Loir Intranasal Immunization with Recombinant Lactococcus lactis Secreting Murine Interleukin-12 Enhances Antigen-Specific Th1 Cytokine Production Infect. Immun., April 1, 2003; 71(4): 1887 - 1896. [Abstract] [Full Text]
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U. M. Padigel and J. P. Farrell CD40-CD40 Ligand Costimulation Is Not Required for Initiation and Maintenance of a Th1-Type Response to Leishmania major Infection Infect. Immun., March 1, 2003; 71(3): 1389 - 1395. [Abstract] [Full Text] [PDF]
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