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Laboratories of
*
Parasitic Diseases and
Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsDiscussionReferences |
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responses
in a substrain (B10.Q-H2-q/SgJ) of B10.Q mice that
manifests as an acute susceptibility to infection by the intracellular
protozoan pathogen, Toxoplasma gondii. Despite robust
systemic production of IL-12, infected B10.Q/J animals fail to mount an
early IFN- response after parasite inoculation. Genetic experiments
revealed that the host resistance and IFN- production defects are
determined by a single autosomal recessive locus distinct from the
Stat4 gene. Nonetheless, a delayed IL-12-mediated IFN-
response emerges in later stages of acute infection but is unable to
prevent host mortality. IL-18 administration restores, in an
IL-12-dependent manner, the early IFN- response and host resistance
of B10.Q/J animals. These in vivo studies indicate that the partially
impaired IL-12 responsiveness in B10.Q/J mice can result in defective
host resistance and demonstrate a therapeutic function for IL-18 in
reversing a genetically based immunodeficiency in IL-12-dependent
IFN- production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsDiscussionReferences |
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A pathway central to host resistance to T. gondii involves
the IL-12/IFN- axis of the cytokine network. Thus, abrogation of the
production or function of either IL-12 or IFN- by Ab neutralization
or by gene targeting results in acute susceptibility to parasite
challenge (4, 5, 6). IFN- operates as a final effector to
activate antimicrobial mechanism(s) within macrophages and other cell
types infected by T. gondii (7, 8). IL-12, in
contrast, functions indirectly as an inductive signal, driving high
level production of IFN- by NK and T lymphocytes
(9, 10, 11). The above notion is supported by the finding that
animals deficient in IFN- or IFN- receptors show no appreciable
resistance to T. gondii, despite copious production of IL-12
(4, 7). Literature published to date indicates nearly
absolute requirement for the IL-12/IFN- axis in host resistance to
systemic T. gondii infection (4, 11, 12, 13). Thus,
the ability of mice to resist T. gondii challenge during
acute infection is a highly stringent test of IL-12/IFN- function
in vivo.
In the accompanying report (14), we documented, using in
vitro and biochemical experiments, a defect in the IL-12 responsiveness
of NK and T cells derived from a subline of the B10.Q mouse maintained
at The Jackson Laboratory (Bar Harbor, ME; B10.Q/J). Here, we further
characterized the IL-12 signaling defect in the B10.Q/J mice, in the
context of the in vivo immune response to T. gondii
infection. Our results indicate that B10.Q/J animals, unlike their
counterparts bred at Taconic Farms (Tarrytown, NY), are highly
susceptible to parasite challenge. This stems from a selective defect
in the IFN- response during the first 4–5 days of infection. The
genetic element controlling defective early IL-12-dependent lymphokine
responses is inherited in a recessive, autosomal fashion and is
distinct from the Stat4 locus. Interestingly, the effects of this
mutation on the IFN- response appear transient and can be corrected
by IL-18 administration. These findings, taken together with the
results in the accompanying study (14), suggest that the
B10.Q/J defect affects a critical element in the IL-12 signaling
pathway.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsDiscussionReferences |
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B10.Q/J (JAX stock no. 002024) and Stat4 gene-targeted (15) mice (backcrossed for 11 generations on the BALB/c background, JAX stock no. 002826) were purchased from The Jackson Laboratory. B10.Q/Ai and IL-12 p40-deficient mice (16) (backcrossed for five generations onto the C57BL/6 strain) were obtained from Taconic Farms through the National Institute of Allergy and Infectious Diseases Animal Supply Contract. Mice of both sexes were used. For experimental infections, sex- and age-matched mice received 20 cysts of the ME49 strain of T. gondii i.p. (11). Host resistance to the parasite was monitored by following the survival of the infected animals as well as by enumerating parasite-infected cells in the peritoneal exudates obtained at 4 or 5 days postinfection as described previously (4).
In vivo treatment with recombinant cytokine and anti-cytokine Abs
Murine rIL-12 (a gift of Genetics Institute, Cambridge, MA) or
murine IL-18 (PeproTech, Rocky Hill, NJ) was administered to mice i.p.
on days 1, 3, and 5 postinfection. Unless otherwise stated, mice
received 1.0 µg IL-18, 0.5 µg IL-12, or PBS in a volume of 0.5
ml/mouse. In some experiments, infected B10.Q/J mice were treated with
mAb directed against IL-12 (C17.8) (17) or
-galactosidase (GL113). Ab (1 mg/dose) was administered i.p. on
either day 2 (in IL-18-treated B10.Q) or day 5 (in untreated B10.Q)
postinfection to assess the role of endogenous IL-12. Serum samples
were obtained by tail bleeding and stored at -20°C until analyzed
for IFN- production.
Splenocyte/peritoneal cell cultures
Splenocytes or peritoneal exudate cells (3 x 106/ml) were cultured in RPMI 1640 (Life Technologies, Gaithersburg, MD) supplemented with 10% FCS (HyClone, Logan, UT), antibiotics, L-glutamine, and 2-ME (5 µM). Splenocyte cultures were left unstimulated or treated with IL-18 (10 ng/ml), IL-12 (1 ng/ml), or a combination of IL-12 and IL-18.
Cytokine measurements
IL-12 p40 and IFN- levels in sera and culture
supernatants were measured using standard ELISA procedures as
previously described (4).
B10.Q/J but not B10.Q/Ai mice are acutely susceptible to T. gondii infection
When infected with 20 cysts of the nonlethal ME49 strain of
T. gondii i.p., immunocompetent mouse strains invariably
resist acute challenge and establish chronic infection. As expected
(18), B10.Q mice purchased from Taconic Farms (B10.Q/Ai)
survived acute T. gondii infection (Fig. 1
A). Remarkably, B10.Q animals
from The Jackson Laboratory (B10.Q/J) exhibited acute susceptibility,
all infected animals succumbing to infection within 10–14 days
postinoculation. This lethality could arise from a defect in host
control of parasite replication (4) or from an excessive
immunopathological response to the pathogen challenge
(19). To distinguish between these two possibilities, the
level of infection was measured in peritoneal cells of resistant and
susceptible B10.Q mice 5 days post-i.p. challenge. Exudate cells
harvested from B10.Q/Ai, as expected, contained very few
tachyzoite-infected cells. In contrast, a very high percentage of
infection was observed in cells obtained from susceptible B10.Q/J (Fig. 1B). The latter observations argue that B10.Q/J mice succumb
to T. gondii infection because of an inability to control
parasite replication.
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but normal IL-12
responses in vivo
To determine whether the acute susceptibility phenotype of B10.Q/J
mice could be explained by deficient Th-1 responses, IL-12 and IFN-
levels were measured in culture supernatants of day 5 peritoneal
exudate cells from both resistant and susceptible B10.Q substrains. As
shown in Fig. 2, cultures from
susceptible mice exhibited a severely blunted IFN- response despite
production of elevated levels of IL-12. Thus, the failure to control
parasite growth in the peritoneal cavity could be explained by the
inappropriately low IFN- produced at this local site of infection.
Measurement of the same cytokines in the serum on d5 revealed a
similarly low IFN- response in the face of greatly enhanced levels
of circulating IL-12 (data not shown and Fig. 3B.). Overall, these in vivo
results are consistent with the observed hyporesponsiveness of B10.Q/J
splenocytes to IL-12 in culture (described in the accompanying paper
(14)).
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A series of mating experiments were performed to characterize the
genetic basis of the B10.Q/J susceptibility phenotype. First, B10.Q/J
mice were mated with their Taconic counterparts, and the susceptibility
of the F1 offspring was assessed. All
F1 animals (regardless of which substrain was
used as male or female parent) were resistant to T. gondii
infection (Fig. 3
A). Thus, the defective resistance of
B10.Q/J mice appears to be due to a recessive gene mutation.
Mutations that functionally compromise components of the IL-12
signaling machinery could explain the observed hyporesponsiveness to
IL-12 of B10.Q/J mice. To date, the protein Stat4 has been implicated
as the major signal transducer mediating the effects of IL-12 in the
immune system and would thus represent an obvious and logical candidate
gene (15, 20). Furthermore, biochemical studies
(14) document defective and delayed phosphorylation of
Stat4 on IL-12 induction. To directly assess whether the B10.Q/J mouse
has an intact and functional Stat4 gene complement, we mated female
B10.Q/J mice with Stat4-deficient animals and determined the resistance
phenotype of the offspring. Whereas both B10.Q/J and Stat4-deficient
(21) parental mice were highly susceptible, all
F1 animals were resistant to T. gondii
infection (Fig. 3A). The ability of the B10.Q/J mouse to
genetically complement the Stat4 null mutation is indicative of an
intact and functional Stat4 gene in the susceptible B10.Q/J mice. Thus,
the defect in Stat4 phosphorylation in B10.Q/J appears to be Stat4 gene
extrinsic.
To further characterize the inheritance pattern of this defect, male
(B10.Q/J x BALB/c Stat4 knockout (KO)) F1
mice were mated to female B10.Q/J mice. Backcross mice were infected
with T. gondii i.p., and the levels of infection in the
peritoneum and serum IFN- were measured in individual mice 4 days
later. As shown in Fig. 3B, 27 of 52 offspring were typed as
susceptible mice (i.e., high parasite load and low serum IFN-). A
majority (25 of 52) of the other mice exhibited a resistant phenotype
(low parasite load and high serum IFN-). The very high frequency of
susceptible mice among the F1 backcross offspring
is consistent with control of this susceptibility trait by a single
major recessive locus (
2 test,
p = 0.78).
B10.Q/J mice exhibit a delayed, IL-12-dependent IFN-
response in vivo
Although B10.Q/J mice exhibit severely defective IFN- responses
to IL-12 stimulation in vitro and early during T. gondii
infection in vivo, a residual lymphokine response is discernible. This
raises the interesting possibility that the defect in IL-12
responsiveness may not be absolute and that a cryptic sensitivity to
IL-12 induction may exist. To explore this question, we measured the
levels of IFN- in the serum of infected mice after the day 5 point
initially assayed. As shown in Fig. 4A, B10.Q/J mice do have the
capacity to mount a systemic IFN- response at later stages of the
acute infection. The levels of lymphokine detected approach and, just
before death, even surpass those observed in resistant B10.Q/Ai mice.
This set of observations illustrates that timely synthesis of
sufficient amounts of IFN- early during infection is critical for
host resistance and suggests that the late production of this cytokine
in the B10.Q/J mice may have little if any host protective
consequence.
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A). This difference suggests that IL-12
may be required for the observed delayed burst of IFN- production.
To directly address whether endogenous IL-12 activity plays an
inductive role in this late phase response, anti-IL-12 or control
Ab was administered to groups of B10.Q/J mice on day 5 post-T.
gondii inoculation. Transient neutralization of endogenous IL-12
decreased the systemic IFN- response on day 7 to levels observed in
IL-12-deficient animals (Fig. 4B). Thus, the late IFN-
response in B10.Q/J is IL-12 dependent. Exogenous IL-18 treatment rescues B10.Q/J defect in early IFN production and acute resistance: dependence on endogenous IL-12
The finding that endogenous IL-12 can induce IFN- production
late but not early during T. gondii infection in B10.Q/J
mice has several implications. First, it indicates the defect in IL-12
responsiveness for IFN- production is not absolute; i.e., the
receptor chains do not have a "lethal flaw" mutation. Instead, the
susceptibility phenotype may stem from quantitative or conformational
deficits in cell surface IL-12 receptors or in cytoplasmic signaling
components that are conditional or modulable. A second implication is
that certain cellular interaction(s) or endogenous mediator(s) emerge
late during the acute phase of T. gondii infection that
ameliorate, if not totally bypass, the passively negative constraint(s)
imposed on IL-12 signaling/responsiveness by the B10.Q/J defective
genetic element. Further, exogenous supplementation of such putative
modulatory factors early during T. gondii infection in
B10.Q/J mice should rescue the defect in IFN- production, in a
manner that is dependent on endogenous IL-12 bioactivity/signaling.
IL-18 is an IL-1-like cytokine capable of inducing IFN- synthesis in
NK, T lymphocytes, and other cell types (22). Although its
own IFN--inducing capacity is modest, IL-18 acts synergistically
with IL-12 to effect high level IFN- synthesis in NK, T, and other
immune cell types. In the accompanying report (14), we
showed that a combination of IL-18 and IL-12, but not each cytokine
alone, induced highly significant levels of IFN production in B10.Q/J
splenocyte cultures. To test whether IL-18 could rescue B10.Q/J mice
from acute susceptibility to T. gondii infection, IL-18,
IL-12, or vehicle was administered on days 1, 3, and 5 i.p.
Remarkably, IL-18-, but not IL-12- or PBS-treated mice mounted an early
IFN- response (Fig. 5C) and
survived acute infection (Fig. 5A). Importantly, host
survival (Fig. 5B) and the early production of IFN- (Fig. 5C) in IL-18-treated B10.Q/J mice were abrogated by
neutralization of endogenous IL-12.
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, in vivo
exposure to IL-18 does not rescue the IL-12-hyporesponsive phenotype of
B10.Q/J cells. IL-18 pretreatment of day 2 T.
gondii-infected B10.Q/J mice did not restore IL-12 responsiveness
ex vivo (data not shown). Significant levels of IFN- production were
observed only upon combined in vitro exposure to IL-18 and IL-12 (Fig. 6). Nonetheless, prior in vivo exposure to IL-18 appears to enhance the
responsiveness of these cells to combined IL-18/IL-12 stimulation
ex vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsDiscussionReferences |
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response pathway have been shown to lead to increased
susceptibility to a number of different intracellular pathogens
(23, 24, 25). In this report, we demonstrate that a heritable
defect in IL-12 responsiveness that has arisen in a substrain (B10.Q/J)
of B10.Q mice results in an extreme and absolute loss of host
resistance to acute infection with T. gondii. At the early
time points assayed, B10.Q/J mice produced very little IFN- and
consequently failed to control parasite replication at the site of
inoculation. This susceptibility phenotype is similar to animals with
null mutations in IL-12, Stat4, or IFN- (4, 5, 21).
However, a characteristic distinguishing the B10.Q/J susceptibility
trait is the later emergence of a robust systemic IFN- response.
Notwithstanding, B10.Q/J mice succumb with the same rapid kinetics as
IL-12- or IFN--deficient mice. This observation underscores the
importance of a prompt IL-12-dependent IFN- response in ensuring
resistance and host survival in the face of an infectious challenge, a
function which in early T. gondii infection is likely to be
provided by NK cells (26).
Whereas the phenotype of acute susceptibility to T. gondii
could readily be explained by the IL-12-hyporesponsive status of the
B10.Q/J mouse, the mechanism(s) underlying their resistance to
autoimmune disease (arthritis) induction may be more complex.
Interestingly, a recent analysis (27) of the mechanisms of
vaccine-induced immunity to the exoerythrocytic, intrahepatic stages of
the malarial parasite has documented the development of an atypical
mechanism of immunity in the B10.Q/J mouse. CD8 T cell IFN-
production is a requisite component of protective immunity to
sporozoite (mosquito stage) challenge in all other mouse strains
studied. In contrast, vaccinated B10.Q/J mice fail to express such an
IL-12 or IFN--dependent mechanism but nevertheless develop a
CD8-based (presumably CTL effector-dependent) protective response. This
finding would further indicate that the deficit in the B10.Q mouse is
narrowly restricted to IL-12-dependent responses and would argue
against a generalized immunodeficiency.
The molecular basis for defective IL-12 responsiveness in the B10.Q/J
mouse remains to be defined. Lymphocyte responses to bioactive IL-12
are mediated by Stat4. To ascertain whether B10.Q mice have a defective
Stat4 gene, these mice were mated to BALB/c Stat4-deficient mice. The
ability of these mice to complement this null mutation indicates the
presence of an intact and functional Stat4 gene in the B10.Q/J mouse.
Indeed direct sequencing of the coding region did not reveal any
consistent mutations (R. Ortmann, unpublished results). Interestingly,
B10.Q/J mice exhibit a delayed but detectable phosphorylation of Stat4
in response to IL-12 in vitro (14). Thus, the B10.Q/J
mouse may harbor homozygous mutations in the IL-12R1, IL-12R2,
tyk2, Janus kinase 2, or another unknown gene locus acting upstream of
Stat4 (28). Positional mapping using the
F1 backcross progeny shown in Fig. 3 should be
useful in identifying the affected gene product.
Regardless of the exact location and nature of the genetic lesion, the
findings reported here indicate that the phenotypic change in the
B10.Q/J strain is sufficiently subtle to allow IL-12 to act as a
partial agonist. Thus, although severely attenuated, IL-12
induced/dependent IFN- production is demonstrable both in splenocyte
cultures and late during acute T. gondii infection. Further,
the induction of high level IFN- production by IL-18 requires
coincubation with IL-12 in vitro and endogenous IL-12 activity in vivo.
Interestingly, a recent study (21) of T. gondii
infection in Stat4-deficient animals has also demonstrated a marked
effect of combined IL-18 and IL-2 treatment on host resistance and
survival of mutant mice. However, the protective efficacy of IL-18/IL-2
was at best partial and transient (i.e., 3–4 day prolongation of
survival time). In contrast, IL-18 treatment not only rescued B10.Q/J
mice from acute mortality but also allowed for the establishment of
chronic infection and host survival beyond 60 days postinfection (Fig. 6A and data not shown). The disparity in outcomes between
IL-18-treated B10.Q/J and Stat4-deficient mice suggests that
biologically relevant IFN--dependent host resistance to T.
gondii mediated by IL-18 requires some level of IL-12/Stat4
function (10, 28). A recent report by Cai et al.
(29) provides direct and further evidence for an auxiliary
role for IL-18 in toxoplasmosis. Thus, although IL-18 was appreciably
induced as early as 3 days postinfection, neutralization of IL-18
decreased IFN- production only transiently and did not result in
decreased resistance to T. gondii infection in SCID
mice.
The molecular mechanism of IL-18 rescue of the B10.Q/J defect in
IL-12-dependent IFN- production and host resistance requires further
analysis. The ability of IL-12 and IL-18 to reciprocally enhance
receptor expression is now well documented (30, 31). It
was plausible that IL-18 may up-regulate IL-12 receptor expression and
therefore increase the IL-12 signaling competence of the B10.Q/J cells.
Such an explanation is not supported by the finding that prior in vivo
IL-18 exposure failed to convert B10.Q/J cells into IL-12 responders ex
vivo. A general explanation for the IL-18 effect is at the level of
cooperative interactions of transacting factors induced by signals
emanating from the two separate receptor systems (32, 33).
Thus, NF-
B activation by IL-18 may partially compensate for an
inefficient IL-12-induced Stat4 (20) and p38
mitogen-activated protein kinase (MAP kinase) (34)
activation in B10.Q cells. Interestingly, unidentified factors that
require de novo protein synthesis, in addition to Stat4 and NF-B
activation, participate in effecting maximal IFN- transcriptional
activity in response to IL-12 and IL-18 (35). An
IL-18-induced factor involved in the synergistic activation of IFN-
gene transcription in CD4-positive lymphocytes has recently been
identified as GADD45 (36). De novo synthesis of this
gene product and downstream activation of p38 MAP kinase appeared to be
selectively required for cytokine (IL-12-IL-18)- but not TCR-induced
IFN- production (36). Potent induction of the
GADD45b-p38 MAP kinase pathway by IL-18 may thus compensate for
deficits in IL-12 signaling and restore IFN- production in B10.Q/J
cells. The signaling intermediates induced by IL-18 may be quite
labile, thus requiring immediate or concurrent exposure to IL-12 for
optimal IFN- production.
Naturally occurring mutations in the IL-12 R 1-chain have been
reported in children who present with disseminated infections
attributable to low virulence mycobacteria or Salmonella
(23, 25). Recessive nonsense or missense mutations in the
coding region result in total loss of NK and T cell surface expression
of the IL-12R 1-chain and, consequently, IL-12 responsiveness.
Similarly, gene targeting of the IL-12R 1- or IL-12R 2-chain gene
in the mouse results in an absolute loss of IFN- response to IL-12
(37, 38). Although it is unclear whether the B10.Q/J mouse
has any mutations in the IL-12R 1 or 2 genes, surface expression
of the 1 and 2 receptors is detectable on B10.Q/J NK and T
lymphocytes ( 14). Further, data presented here indicate
that the autosomal recessive defect in the B10.Q mouse
spares some measure of IL-12 signaling, presumably acting via
ligation of the conventional, heterodimeric IL-12 receptor.
This phenotype may be analogous to the partial deficiency in IFN-
signaling previously reported in children with a nonlethal form of
disseminated mycobacterial infection (24). If so, our
data suggest that IL-18 administration may be potentially beneficial
for treating such immunodeficiency states (39).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alan Sher, Laboratory of Parasitic Diseases, Building 4, Room 126, Center Drive, Bethesda, MD 20892-0425.
3 Abbreviations used in this paper: KO, knockout; MAP kinase, mitogen-activated protein kinase.
Received for publication January 12, 2001. Accepted for publication March 1, 2001.
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-2 (IL-12R2)-deficient mice are defective in IL-12 mediated signaling despite the presence of high affinity IL-12 binding sites. J. Immunol. 165:6221.1 (IL-12R1): evidence for an IL-12R-1-independent pathway of IL-12 responsiveness in human T cells. J. Exp. Med. 192:517.This article has been cited by other articles:
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  N. Tokumasa, A. Suto, S.-i. Kagami, S. Furuta, K. Hirose, N. Watanabe, Y. Saito, K. Shimoda, I. Iwamoto, and H. Nakajima Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-{gamma} production and the induction of Th1 cell differentiation Blood, July 15, 2007; 110(2): 553 - 560. [Abstract] [Full Text] [PDF]
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 J. A. Gracie, S. E. Robertson, and I. B. McInnes Interleukin-18 J. Leukoc. Biol., February 1, 2003; 73(2): 213 - 224. [Abstract] [Full Text] [PDF]
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R. Ortmann, R. Smeltz, G. Yap, A. Sher, and E. M. Shevach A Heritable Defect in IL-12 Signaling in B10.Q/J Mice. I. In Vitro Analysis J. Immunol., May 1, 2001; 166(9): 5712 - 5719. [Abstract] [Full Text] [PDF]
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).
n = 10 per group. B, Percentage of
tachyzoite-infected peritoneal cells observed in B10.Q/J or B10.Q/Ai
mice on day 5 post-T. gondii inoculation. Data are
means ± SE of five mice sampled and are representative of at
least three similar experiments.
) mice were infected with T.
gondii and bled on days 0, 4, 6, and 8 postinfection. Data
represent means of IFN-
). Survival of mice was monitored for at
least 30 days. B, Groups of five T.
gondii-infected IL-18-treated (on days 1, 3, and 5) B10.Q/J
mice were also injected on days 2 and 4 with GL-113 control Ab (