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*
Department of Immunology and
Experimental Animal Center, The Weizmann Institute of Science, Rehovot, Israel;
Sourasky Medical Center, Tel-Aviv, Israel; and
Section of Immunobiology, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IL-4, cells from Ii-/- mice secrete mostly IFN-.
Moreover, Ii-/- mice exhibit a normal Th1 response in the
delayed-type hypersensitivity and trinitrobenzene sulfonic acid
colitis models; however, these mice lack an in vivo Th2 response, as
demonstrated in the asthma model. Therefore, we suggest that defective
Ag presentation in Ii-/- mice leads selectively to a Th1
effector response. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and 
-chains with trimers of the
invariant chain (Ii) (4). Briefly, three dimers
bind sequentially to a trimer of the Ii to form a nonameric complex
(Ii)3 (5, 6, 7), which then exits
the ER. After being transported to the trans-Golgi, the
Ii complex is diverted from the secretory pathway to the
endocytic system (8, 9, 10, 11) and ultimately to acidic
endosome/lysosome-like structures called MHC class II compartments
(12, 13, 14, 15, 16). Once in this pathway, the luminal domain of the
Ii is proteolytically degraded, leaving a small fragment, the class
II-associated Ii peptide (CLIP), which is bound to the released
dimers. Interaction of the CLIP complexes in the specialized
lysosome-like compartment with another class II-related
molecule, HLA-DM in humans and H2-M in mice, drives out the
residual CLIP, ultimately rendering the dimers competent to bind
antigenic peptides derived from internalized Ags that are also
delivered to the endosomes (17, 18). The peptide-loaded
class II molecules then leave this compartment by an unknown route to
be expressed on the cell surface, where they encounter
CD4+ T cells. It has become possible to analyze the role of Ii in authentic class II-positive cell types using Ii-deficient mice (Ii-/-) generated by gene targeting. Cells from mutant mice show aberrant transport of MHC class II molecules, resulting in reduced levels of class II complexes at the surface, which do not have the typical compact conformation indicative of tight peptide binding. Although these complexes do not bind endogenously processed Ags, class II molecules that reach the surface are able to bind exogenous peptides added to the medium. In addition, deletion of the Ii gene was found to greatly diminish the ability of splenic APCs to present exogenous protein Ag in a class II-restricted fashion in vitro and to reduce the CD4+ T cell maturation in vivo (19, 20, 21). Ii-/- mice clearly have deficiency in the CD4+ T cell compartment as a result of defective positive selection in the thymus. More specifically, their CD4+ T cells express high levels of CD44 and CD69 and low levels of TCR and CD45RB (22, 23). This activated phenotype may result from an abnormal selection of CD4+ T cells. Alternatively, the high percentage of phenotypically mature CD4+ cells could reflect the low number of CD4+ T cells in the periphery that responded to a normal antigenic load and therefore developed a high percentage of cells with a memory or activated phenotype.
In this study, we have investigated the in vitro and in vivo
immune responses of T cells in Ii-/-. Our
results have demonstrated that CD4+ T cells from
Ii-/- mice can proliferate normally in vitro
after in vivo immunization with protein Ags. However, cytokine
secretion profiles of Ag-primed CD4+ T cells from
Ii-/- mice are quite different from
CD4+ T cells from wild-type mice. Whereas cells
from wild-type mice secrete IFN- and IL-4, cells from
Ii-/- mice secrete mostly IFN-. Moreover,
Ii-/- mice exhibit a normal Th1 response in
vivo in delayed-type hypersensitivity (DTH) and trinitrobenzene
sulfonic acid (TNBS) colitis models; however, they failed to
show a Th2 response in vivo using the OVA asthma model.
Importantly, these results suggest that the efficiency of Ag presentation dictates the nature of the immune response and that inefficient Ag presentation in Ii-deficient mice leads to a preferential Th1 response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (control), Ii-deficient on a C57BL/6 background (Ii-/-) (21) and p41 transgenic on the C57BL/6 Ii-/- background (p41), mice (22) were used in this study. The Animal Research Committee at the Weizmann Institute of Science (Rehovot, Israel) approved all animal procedures.
Immunization and CD4+ T cell priming
Three to five mice were immunized with 100 µg of keyhole limpet hemocyanin (KLH) (Calbiochem, La Jolla, CA) in a 1:1 emulsion with CFA containing 1 mg/ml Mycobacterium tuberculosis strain H37Ra (Difco Laboratories, Detroit, MI) injected in the hind footpads. After 9 days, the draining lymph nodes were removed and cell suspensions were prepared.
In vitro proliferative recall response
After total lymph node cells were removed 9 days after injection, the cells were cultured in 96-well plates at 5 x 105 cells/well in Bruff medium supplemented with 5% FCS, 2 mM of glutamate, 100 U/ml penicillin, 100 µg/ml streptomycin, and different concentrations of KLH. Approximately 1 x 105 purified CD4+ T cells were incubated with 5 x 105 irradiated wild-type APCs in triplicates in 96-well plates with increased concentrations of KLH. Proliferation was measured by adding of 1 µCi of [3H]thymidine (International Chemical and Nuclear, Irvine, CA) in the last 18 h of a 4-day culture.
Purification of CD4+ T cells
Total CD4+ T cells were isolated from spleen and lymph nodes by negative selection as previously described (24).
Cytokine ELISA analysis
ELISAs were performed using anti-IL-4 or anti-IFN- as
the primary Ab and the corresponding biotinylated anti-IL-4 and
IFN- mAbs (BD PharMingen, San Diego, CA), following the
recommended protocol.
Polyclonal stimulation
CD4+ T cells were cultured in the presence of irradiated wild-type APCs in the presence of different concentrations of Con A or anti-CD3. Proliferation was determined after 4 days by incorporation of [3H]thymidine.
DTH response
Mice were immunized in the dorsal flanks with 100 µg of KLH in CFA. Five days later, soluble KLH (10 µg) was injected in the right ear and PBS in the left ear. Ear swelling was measured 24 h later.
OVA sensitization and challenge
C57BL/6 (control) and Ii-/- mice were immunized i.p. on days 0, 7, and 14 with 10 or 100 µg of chicken egg albumin (OVA; Sigma-Aldrich, St. Louis, MO) mixed with 2 mg of aluminum hydroxide (Pierce, Rockford, IL) in 300 µl of PBS. Beginning on day 15 after the initial sensitization, the animals were challenged every day for 5 days (days 15–19) by inhaling 4% OVA in PBS, administered by an ultrasonic nebulizer (DeVilbiss, Somerset, PA) for 20 min. For each inhalation, the animals were placed in a 0.5-L plastic chamber connected to the nebulizer.
Bronchoalveolar lavage (BAL)
BAL was performed on day 19, 4 h after the last OVA challenge. After deep anesthesia with 2,2,2 tribromoethanol solution, a midline celiotomy was done, and the animals were euthanized by exsanguination by withdrawal of blood from the inferior vena cava. A 21-gauge needle was inserted into the proximal trachea and secured with a 3-0 silk suture. The lungs were lavaged via the tracheal needle with 4 x 1 cc of 0.9% NaCl for cytospin slides.
Lung histology
The lungs were inflated with 1 ml of 10% formalin until distended. Samples for paraffin sectioning were immersed in 10% formalin for fixation for 48 h. The tissues were then embedded in paraffin and 2- to 3-µm sections were cut and stained with H&E for viewing by light microscopy.
Induction of colitis
Wild-type and Ii-/- mice were anesthetized for 120 min, received by intrarectal administration of 75 µl of the hapten TNBS solution (trinitrobenzene sulfuric acid; Sigma-Aldrich) dissolved in distilled water (150 mg/kg) and mixed with an equal volume of ethanol (50% ethanol). The animals were killed by cervical dislocation 3–5 days after TNBS administration.
Macroscopic and histologic assessment of colitis
The colon was examined under x5 magnification to evaluate the macroscopic lesions according to the Wallace criteria. The Wallace score ranks macroscopic colon lesions on a scale from 0 to 13 based on criteria reflecting inflammation, such as hyperemia, thickening of the bowel, and the extent of ulceration (25, 26). The colon was cut lengthwise and fixed overnight in 10% paraformaldehyde acid and embedded in paraffin, stained with H&E, and examined randomly by a pathologist and ranked according to the Ameho criteria (27). This score, on a scale from 0 to 6, takes into account the degree of the inflammatory infiltrate, the presence of erosion, ulceration or necrosis, and the depth and surface extension of the lesions.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been shown previously that, in the absence of Ii, total
lymph node cells (LNCs) responded poorly to immunization with exogenous
proteins (19, 22, 28, 29, 30). Briefly, control (C57BL/6) and
Ii-/- mice were immunized with KLH, and their
total LNCs were analyzed for their recall response. As expected, LNCs
from mice lacking Ii proliferated poorly compared with control cells
after immunization (Fig. 1
A).
The low proliferative response could be explained by inefficient
selection of CD4+ T cells in the absence of Ii,
which could result in a lower precursor naive T cell frequency for a
given Ag (28) or in T cells with TCRs of lower avidity.
Alternatively, the weak response could reflect the low level of the
total CD4+ T cell population, which is otherwise
normal in the periphery of Ii-/- mice, or the
poor Ag presentation by the Ii-/-
APCs.
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B) or anti-CD3 mAbs (Fig. 1C), and
their proliferation was measured. As was previously shown
(28), both populations proliferated almost the same under
these conditions. These results showed that the
Ii-/- CD4+ T cells were
competent to transduce a mitogenic signal and could respond to this
signal at a level comparable to the wild-type cells.
To analyze the responsiveness of Ii-/-
CD4+ T cells to antigenic protein, we injected
control (C57BL/6) and Ii-/- mice with KLH/CFA.
Nine days later, CD4+ T cells were purified from
draining lymph nodes and analyzed for their recall response to KLH.
Equal numbers of control and Ii-/-
CD4+ T cells were incubated in the presence of
wild-type splenic APCs in the presence of different concentrations of
KLH. As shown in Fig. 2A,
control and Ii-/- CD4+ T
cells had a similar proliferative response. Furthermore, no difference
in proliferation was detected when these CD4+ T
cells were titrated in the presence of control APCs and 10 µg/ml of
KLH (Fig. 2B). These results implied that the low numbers of
CD4+ T cells from the
Ii-/- mice were selected efficiently. These
Ii-/- CD4+ T cells were
qualitatively similar and showed a response to Ag similar to the
control T cells. Therefore, the low proliferative responsiveness of
total LNCs is probably due to the low numbers of the
CD4+ T cells in the periphery of the
Ii-/- mice.
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Surprisingly, although T cell proliferation was indistinguishable
between the control and Ii-/- mice, analysis of
cytokines secreted by the KLH/CFA-primed CD4+ T
cell populations in the recall response to KLH revealed significant
differences. Whereas wild-type CD4+ T cells
secreted a mixture of IFN- and IL-4, Ii-/-
CD4+ T cells did not produce any detectable IL-4
(Fig. 3A) and instead secreted
higher levels of IFN- than those of the wild-type T cells (Fig. 3B). These results suggested that, although the
CD4+ T cells from both mice had the same ability
to respond to Ag by proliferating, they were skewed to differentiate
into different effector populations. Specifically, the results
suggested that when a mixed population of Th1 and Th2 effector cells
had been elicited in the wild-type mice, in the absence of Ii, most of
the cells were Th1. To determine whether CD4+ T
cells from the Ii-/- mice had the intrinsic
potential to become either Th1 or Th2 cells, we isolated and stimulated
total CD4+ T cells from wild-type or
Ii-/- to differentiate with Con A with or
without IL-4, a Th2-inducing cytokine, or IL-12, a Th1-inducing
cytokine. After 4 days, the cells were washed and restimulated with Con
A for 24 h. The supernatant was then analyzed for cytokine
production. CD4+ T cells from both groups
secreted IL-4 and IFN- (Fig. 3D), therefore implying that
CD4+ T cells from Ii-/-
had the same potential to become effector CD4+ T
cells from the wild-type mice and that the skewing in the T cell
effector population is probably due to defective peripheral Ag
presentation or a different cytokine profile in the peripheral lymph
nodes.
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To determine whether the skewing to the Th1 population
occurs in vivo, we monitored the Th1 and Th2 responses in
Ii-/- mice. For Th1, we used the DTH and TNBS
colitis models. DTH is a form of cell-mediated immunity elicited by Ag
in the skin, which is mediated by the inflammatory
CD4+ (Th1) cell. The in vivo DTH responsiveness
of Ii-/- and wild-type mice was analyzed by
immunizing both groups with 100 µg of KLH in CFA in the dorsal
flanks. As shown in Fig. 4, 5 days later
soluble KLH (10 µg) was injected in the right ear and PBS in the left
ear. Ear swelling was measured 24 h later. The magnitude of the
DTH response in the Ii-/- mice by the fifth day
after injection almost reached wild-type levels (p
value of KLH vs PBS of control or Ii-/- <
0.01). The fact that the DTH response reached almost normal levels
suggested that the in vivo CD4+ Th1 cell response
is only marginally affected in the Ii-/- mice.
To further evaluate the in vivo Th1 response in
Ii-/- mice, we used the TNBS colitis model.
Inflammatory bowel diseases are a group of diseases characterized by
chronic destruction of the colon (in ulcerative colitis) or the small
and large bowel (in Crohn’s disease), due to the transmural
infiltration of the bowel wall by a mixed inflammatory infiltrate. This
model is particularly useful in elucidating the primary role of the
CD4+ Th1, because Th1 response induces fatal,
acute, transmural, and focal types of lesions in the early stage of the
disease, whereas Th2 response plays a role only in the later stages of
the disease (31). We have studied the early stage of the
disease by intrarectal installation of TNBS to control and
Ii-/- mice. The mice were killed 3–5 days
after TNBS administration, and macroscopic and microscopic evaluations
were performed. The specimens were given a macroscopic score from 0 to
13 based on the Wallace criteria and a microscopic score based on the
Ameho criteria. All groups (wild-type and Ii-/-
mice) exhibited a transmural inflammatory infiltrate of neutrophils,
macrophages, and lymphocytes (Fig. 5A). There were no significant
differences in the Ameho or Wallace scores (Fig. 5B). These
results further proved the normal in vivo Th1 response of
Ii-/- mice.
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The in vivo Th2 responsiveness of Ii-/-
mice was evaluated by analyzing their response to an OVA challenge in
an asthma model. Asthma is a chronic inflammatory disorder of the
airways characterized by intermittent episodes of dyspnea due to airway
obstruction. The inflammatory response in the asthmatic lung is
characterized by infiltration of the airway wall with lymphocytes and
eosinophils. Recent advances suggest that the T lymphocytes, and in
particular CD4+ T cells, producing the Th2
pattern of cytokines have a major effect in the pathogenesis of this
disease (32, 33, 34, 35). Control and
Ii-/- were immunized with 10 µg of OVA (days
0, 7, and 14) and then were given OVA inhalations for five consecutive
days (days 15–19). Inflammatory cell recruitment in the BAL and
histologic lung sections of the control and
Ii-/- mice was compared. As shown in Fig. 6A, the inhalation of
aerosolized OVA caused a massive infiltration of eosinophils into the
BAL of control mice, whereas the same challenge caused no inflammatory
response in the Ii-/- mice (82.3% control vs
1.76% Ii-/-; p = 1.7 x
10-10).
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B). Microscopic slides
were examined randomly by a pathologist, and an inflammatory score from
0 to 4 was given (0, no inflammatory infiltrate; 1, slight accumulation
of scattered inflammatory cells; 2, mild homogeneous infiltrate; 3,
moderate homogeneous infiltrate; 4, severe inflammation). The
inflammatory infiltrate in the C57BL/6 group was significantly high;
however, almost no inflammatory response was detected in the
Ii-/- group (control 3.33 vs
Ii-/- 0.25; p = 9.6 x
10-5) (Fig. 6C). To determine whether
the reduced inflammatory response was due to ineffective priming of the
T cells, the OVA doses injected into the mice were increased (Fig. 6D). A 10-fold increase in the OVA dosage injected caused no
peribronchial or perivascular inflammation in Ii-deficient mice (55.8%
control vs 1.85% Ii-/-), suggesting a severely
defective in vivo CD4+ Th2 response in
Ii-/- mice.
Besides the Ii role in Ag presentation, we have previously demonstrated
that B cells derived from Ii-deficient mice are arrested at the
immature stage (36, 37). To determine whether the B cell
population affects the skewing to the Th1 population in the
Ii-/- mice, we have analyzed the inflammatory
response to OVA in the Ii-/-, which have been
reconstituted with transgenically expressed low levels of Ii p41
isoform (p41 mice) (22). The low levels of Ii expressed in
these mice are sufficient to fully reconstitute the T cell repertoire,
which exhibits a normal recall proliferative response
(22). CD4+ T cells derived from
these mice proliferate similarly to control and
Ii-/- cells (Fig. 2B) and secrete
IL-4 in the recall response to KLH (Fig. 4C); however, these
low levels cannot mediate the full B cell differentiation in the
spleen, and the B cells are arrested at the immature stage
(36). As shown in Fig. 6, C and D,
the inhalation of aerosolized OVA caused a massive infiltration of
eosinophils into the BAL of the p41 transgenic mice. Histopathologic
examination of the lung tissue from OVA-challenged p41 mice revealed a
pleomorphic peribronchial and perivascular infiltrate consisting of
eosinophils, macrophages, lymphocytes, and neutrophils (Fig. 6B). These results suggest that the Ag presentation, and not
the B cell developmental stage, controls the skewing to the T cell
effector population.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Notably, we have found that the main difference between the wild-type
and Ii-/- CD4+ T cells is
in their cytokine secretion. Whereas wild-type cells secrete IFN-
and IL-4, CD4+ T cells from
Ii-/- mice secrete mostly IFN- and only low
doses of IL-4. This result could be explained as follows. First, these
T cells were selected differently in the thymus; Ag presentation in the
thymus is probably affected by the lack of Ii, and therefore these
cells might be selected with TCRs that intrinsically caused a
propensity to yield Th1 effector cells. For example, if only
high-affinity T cells were selected as a result of limiting MHC-peptide
in the thymus, such cells may yield Th1 cells upon activation in the
periphery. Alternatively, the naive T cell repertoire might be normal,
but the priming environment of the immune response might be different
in the two strains and the T cells could have been affected by the dose
of the Ag, the type of APC, the costimulatory pathways
(38, 39, 40, 41, 42), and the cytokine environment
(43, 44, 45), all of which have been postulated to be some of
the polarizing factors. Our findings support the theory that
Ii-/- T cells are selected qualitatively,
similarly to wild-type cells. We have shown that
CD4+ T cells from both
Ii-/- and wild-type mice can produce IL-4 or
IFN- in the presence of polarizing cytokines. Therefore, we suggest
that the T cells have no intrinsic difference in their ability to
become either Th1 or Th2 and that they were probably not selected
differently. We favor the hypothesis that the lymphoid microenvironment
or the way the Ag is presented during the immune response might
influence the differentiation of the cells into a given effector T cell
population. Bretscher et al. (38) and Hosken et al.
(40) previously proposed that low to moderate doses of Ag
presented to CD4 naive T cells would switch their development into a
Th1 effector response, whereas very high or very low doses of Ag
presented would switch their response into a Th2 effector response. The
absence of Ii alters the nature of peptide binding to class II
molecules. Specifically, the few class II complexes that escape the ER
have an aberrant conformation, forming no compact dimers and instead
floppy dimers are observed (19, 20, 21). The compact conformer
seen in the wild-type mice probably bears a tightly bound peptide, but
the floppy form found in the Ii-/- mice is
likely to be empty or to carry a low-affinity peptide in a loosely
bound state. Most proteins are probably presented less efficiently or
are not presented at all in the Ii-/- mice.
Defective Ag presentation in Ii-/- mice might
lead selectively to Th1 effector CD4+ T cells,
possibly as a result of the delivery of a low antigenic signal.
The fact that Ii-/- mice have an almost normal DTH response 5 days after injection supports the finding that these mice have a higher percentage of Th1 cells. These Th1 cells, which are the main effector CD4+ T cell population that can be found in the Ii-/- mice, respond effectively to antigenic stimulation. Our results in the TNBS colitis model, exhibiting a known Th1-dependent inflammatory response (31), show a similar inflammatory colitis reaction in both the wild-type and Ii-/-. Thus, these results strengthen our conclusion that, although Ii-/- mice have a low CD4+ T cell population, their Th1 response is normal.
Ii-/- mice exhibit a complete loss of OVA-challenged response in the asthma model. These results could be explained by the lack of IL-4 secretion in the in vitro studies, indicating that Ag presentation might be a crucial factor in the skewing to one effector cell population. Alternatively, the lack of a Th2 response might be attributed to the lack of a mature B cell population in the Ii-deficient mice. Previously we have shown that B cells do not mature normally in mice lacking Ii. These mice accumulate IgMhigh, CD23low, heat-stable Aghigh, and IgDlow immature B cells in their periphery, which mediates a low T-independent Ab response (36, 37). Thus, B cells might play an important role in this model. The role of B cells in T cell priming is still controversial. Several studies have revealed a critical role for B cells in the T cell response in vivo (46, 47, 48). These results were challenged by reports showing that the absence of B cells had little impact on CD4+ T cell proliferation and cytokine production in response to protein Ags (49, 50, 51). More recently, a few studies have suggested that B cells are not required for T cell sensitization but play a role in the induction of IL-4 gene expression (52, 53, 54). In this study, we show that transgenic mice expressing the Ii p41 isoform exclusively on the Ii-/- background (22), which have a normal T cell population but a defect in their B cell differentiation, could develop a normal T cell activation and eosinophils infiltration in response to OVA stimulation. In addition, it was previously reported that B cell-deficient mice (µMt-/-) exhibited a normal T cell activation and eosinophils infiltration in the peribronchial regions of the airways, with signs of eosinophil activation and degranulation (55). Therefore, we conclude that defective Ag presentation in mice lacking Ii might lead selectively to Th1 effector CD4+ T cells, possibly as a result of the delivery of low antigenic signal.
Previously, Brown et al. (56) studied the T helper
differentiation in mice lacking Ii. They analyzed the response of
C57BL/6 and BALB/c Ii-/- mice to
Leishmania major and followed their
CD4+ T cell differentiation. Control of the
disease is dependent on class II-restricted Th1 cells and their
production of IFN-, which is required to activate macrophages to
restrain intracellular replication of the organism. In contrast to most
strains of mice, BALB/c animals are unable to contain L.
major due to the development of an aberrant Th2 response during
infection (57). In their studies, it was shown that
C57BL/6 Ii-deficient mice controlled L. major infection
similarly to wild-type mice and had a normal Th1 subset. In addition,
BALB/c Ii-/- mice exhibited a progressive
course of infection and Th2 effector cell development that were
comparable to that seen in the wild-type mice. Therefore, their
conclusion was that Ii-deficient mice develop both Th1 and Th2
responses. The ability of Ii-/- mice to mount a
Th2 response contradicts the results presented in this study, which
could be addressed by several explanations. First, the ability of
Ii-deficient mice to develop the various effector populations was
analyzed in two strains of mice: C57BL/6 and BALB/c. It was previously
concluded that MHC genotypes predetermine Th phenotype based upon the
selection of TCR affinity (58). Therefore, these two
strains respond differently to Ag stimulation and their outcome
effector populations vary. Our studies focused only on the C57BL/6
background, and the differences observed are correlated to the
inability of this strain to respond equally to various treatments. It
will be interesting in the future to follow the skewing of the effector
populations in the BALB/c strain with these different treatments.
Furthermore, L. major is an obligate intracellular parasite
that infects the phagocyte system. The parasite replicates
productively only in the host’s macrophages within an endolysosomal
compartment that contains MHC class II molecules. Whereas we used an
exogenous Ag in a measured dose, Brown et al. (56)
used a replicating parasite in a susceptible genus (BALB/c). Therefore,
continuous parasite replication exposes the mice to very high doses of
Ag, which might enable sufficient Ag to be presented and to overcome
the block on Th2 differentiation.
In conclusion, our results suggest that the low levels of CD4+ T cells in the periphery of the Ii-/- mice are selected appropriately in the thymus and respond equally to the Ag in the periphery when compared with wild-type mice. However, the immune response of these mice is skewed to a Th1 response in vitro and in vivo, probably due to aberrant Ag presentation in the Ii-/- mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Idit Shachar, Department of Immunology, The Weizmann Institute of Science, 1 Herzel Street, Rehovot 76100, Israel. E-mail address: Idit.Shachar{at}weizmann.ac.il
3 Abbreviations used in this paper: ER, endoplasmic reticulum; Ii, invariant chain; CLIP, class II-associated Ii peptide; DTH, delayed-type hypersensitivity; TNBS, trinitrobenzene sulfonic acid; KLH, keyhole limpet hemocyanin; BAL, bronchoalveolar lavage; LNC, lymph node cell.
Received for publication September 5, 2001. Accepted for publication December 10, 2001.
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L. Flaishon, I. Topilski, D. Shoseyov, R. Hershkoviz, E. Fireman, Y. Levo, S. Marmor, and I. Shachar Cutting Edge: Anti-Inflammatory Properties of Low Levels of IFN-{gamma} J. Immunol., April 15, 2002; 168(8): 3707 - 3711. [Abstract] [Full Text] [PDF]
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