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* Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan;
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kanagawa, Japan; and
Department of Pathology, Ehime University School of Medicine, Ehime, Japan
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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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OX40L, a molecule that we originally identified as human gp34 whose expression is induced by the tax gene of human T cell leukemia virus (HTLV)-I (7), is expressed on activated T cells (7, 8, 9, 10, 11), activated B cells (12, 13), dendritic cells (14, 15, 16), and endothelial cells (17), while its receptor, OX40, is primarily known to be a T cell activation marker (18, 19). We and others independently generated OX40L-deficient mice, in which significant impairment of APC functions, leading to reduction in T cell proliferative responses and production of both Th1 and Th2 cytokines, were revealed (16, 20). An important avenue in which OX40/OX40L may participate is in regulating the development and survival of memory CD4+ T cells (21, 22, 23). Recently, we have shown that after adoptive transfer of encephalitogenic wild-type (WT) T cells to OX40L-deficient mice, the mice were apparently unable to sustain disease progression despite showing comparable onset and severity of disease to WT recipient mice (24). Furthermore, OX40 stimulation has been reported to prevent peripheral tolerance of CD4+ T cells (25), suggesting a possible involvement of the OX40/OX40L system in regulating autoimmunity. Indeed, expression of OX40 and/or OX40L has been demonstrated in the tissues of several immune disorders such as experimental allergic encephalitis (24, 26, 27, 28), experimental inflammatory bowel diseases (IBDs) (29, 30), graft-vs-host disease (31, 32, 33), human proliferative lupus nephritis (34), rheumatoid arthritis (35, 36), human IBD (37, 38), human inflammatory muscle diseases (39), and in thymoma of patients with myasthenia gravis (40). In vivo blockade of OX40/OX40L interaction has been described not only to suppress ongoing experimental allergic encephalitis (28) and graft-vs-host disease (32, 41), but also to ameliorate ongoing colitis in murine models of IBD (29, 30), asthma (42), and collagen-induced arthritis (35). These data suggest that OX40/OX40L interaction may play a definitive role in the immune regulation of various immune-related diseases.
To evaluate the influence of constitutive interaction between OX40 and OX40L during immune regulation, we constructed mice stably expressing OX40L on T cells, in which sustained OX40 signaling can occur. In this paper, we demonstrate convincing evidence showing the direct involvement of OX40/OX40L interaction in the development of autoimmunity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The transgene was generated by inserting the cDNA encoding mouse OX40L into the T lineage-specific vector p1017 (43) that carries the mouse lck proximal promoter. The vector was released as a NotI fragment encompassing the tissue-specific transcription unit. The fragment, purified by standard protocols, was microinjected into the pronuclei of (C57BL/6 x DBA/2)F1 fertilized eggs. We obtained three independent founders, in which the presence of the transgene was confirmed by PCR. The founders were then mated with C57BL/6 mice to generate OX40L-Tg offspring, and germline transmission was verified either by PCR with DNA from tail biopsy specimens or by flow cytometric analysis with peripheral blood from the tail vein. The OX40L-Tg mice were backcrossed at least 12 times onto the C57BL/6 and 9 times onto the BALB/c backgrounds.
Mice
OX40L-deficient mice were described previously (16) and had been back-crossed onto the C57BL/6 strains at least 12 times. Age and sex-matched WT littermates of the OX40L-Tg mice or OX40L-deficient mice were used as control mice. Recombination-activating gene (RAG)2-deficient mice on the C57BL/6 background, lacking B and T cells, were obtained from the Central Institute for Experimental Animals (Kawasaki, Japan). The appropriate strain combinations were taken into account in all experiments. All the mice were kept under specific pathogen-free conditions.
FACS analysis
Preincubation with normal rat serum was conducted to prevent labeled mAbs from nonspecific association. The cells were incubated with labeled mAbs for 30 min at 4°C. The samples were then washed with PBS and analyzed with a FACSCalibur flow cytometer (BD Immunocytometry Systems, Mountain View, CA). The analyses were conducted using the CellQuest program (BD Immunocytometry Systems). CD3, CD8, CD4, CD44, and L-selectin (CD62L) were obtained from BD PharMingen (San Diego, CA). MGP34 mAb specific for mouse OX40L was described previously (16). The cells labeled with the biotinylated mAb were visualized by streptavidin-allophycocyanin (BD PharMingen, San Diego, CA), and subjected to flow cytometric analysis. Cells, which were preincubated with unlabeled MGP34 to abolish any specific staining by the biotinylated MGP34, were used as a negative control for OX40L expression.
In vivo T cell priming and recall responses to protein Ags
OX40L-Tg mice or WT littermates were immunized with 100 µg
keyhole limpet hemocyanin (KLH) in the presence of CFA to each hind
footpad. Alternatively, these mice were i.p. immunized with 1 mg KLH in
PBS in the absence of adjuvant. Fourteen to 30 days afterwards,
CD4+ T cells (1 x
105, purity >98%) purified from the popliteal
lymph node or spleen using autoMACS (Miltenyi Biotec, Bergisch
Gladbach, Germany) were incubated with the indicated dose of KLH in the
presence of APCs (5 x 105) at 37°C for
48 h. The APCs used were irradiated (3000 rad) splenocytes derived
from unimmunized WT littermates. The cultured cells were assayed for
[3H]thymidine uptake and cytokine production as
described previously (16). For cytokine production,
culture supernatants were collected at 48 h for IL-2 and IL-4, or
at 72 h for IL-5, IL-10, Il-13, and IFN-
, and subjected to
ELISA.
ELISA
Cytokine levels in tissue culture supernatants or in mice sera
were assayed using ELISA kits for IL-2, IL-4, IL-5, IL-10, IFN- (BD
PharMingen), and IL-13 (R&D Systems, Minneapolis, MN) according to the
manufacturer’s recommendations.
In vivo clonal T cell deletion induced by Staphylococcus aureus enterotoxin B (SEB) injection
A total of 100 µg of SEB (Toxin Technology, Sarasota, FL) was
injected i.p. into 8- to 10-wk-old mice. Peripheral blood from the tail
vein was analyzed by flow cytometry on the indicated days. Cells were
stained with CD4-PE in combination with anti-V
8-FITC (BD
PharMingen) or anti-V6-FITC (BD PharMingen). The ratios of
V8+CD4+ and
V6+CD4+ cell populations
to whole CD4+ cell populations in the peripheral
blood were monitored.
ELISA of serum Igs
The levels of the different Ig subclasses in the various mice sera were assayed as previously described (16). In brief, diluted sera from OX40L-Tg or WT mice were added to 96-wells coated with either goat anti-mouse Ig Ab (Southern Biotechnology Associates, Birmingham, Al), salmon sperm dsDNA (Sigma-Aldrich, St. Louis, MO), or ssDNA and incubated for 2 h at room temperature. The ssDNA was prepared by boiling salmon sperm dsDNA for 5 min. After washing, bound Abs were detected by incubation with either goat anti-mouse IgM, IgG1, IgG2a, IgG2b, IgG3, or IgA conjugated to alkaline-phosphatase (Southern Biotechnology Associates). Color reactions using alkaline-phosphatase substrate (Sigma-Aldrich) were then evaluated by reading OD450. This was demonstrated to be well within the linear part of the titration curve.
Histopathological analysis
Animals were sacrificed at the indicated age. The main organs and tissues that included the heart, lung, aorta, liver, pancreas, submandibular glands, stomach, small and large intestines, spleen, thymus, cervical lymph nodes, tibial bones, kidneys, and ankle joints were processed for histopathological examination. Tissues were next fixed in 10% formalin in 0.001 M phosphate buffer (pH 7.2) and embedded in paraffin (Wako Pure Chemical, Osaka, Japan). In the case of tibial bones and ankle joints, these tissues were decalcified in 10% formic acid. Two- to 4-µm thick sections were prepared and stained with H&E using standard techniques and examined by light microscopy.
Adoptive transfer of CD4+ T cells
Single-cell suspension was prepared from the spleens of the OX40L-Tg or WT littermates, and incubated with mouse CD4 MicroBeads (Miltenyi Biotec) for 20 min at 4°C and subjected to an autoMACS (Miltenyi Biotec). The purified WT or OX40L-Tg CD4+ T cells (purity >99%) were i.v. injected (1–5 x 106) into the syngenic RAG2-deficient mice. Between 2 and 5 wk after the transfer, some recipient mice were sacrificed, and selected tissues were extracted for histopathological analysis. The body weights of the recipient mice were monitored after inoculation.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Three independent OX40L-Tg mouse lines were generated by using the
T cell-specific p1017 expression vector that carries the mouse
lck proximal promoter (43). Flow cytometric
analysis of whole thymocyte populations derived from the three OX40L-Tg
lines, but not from the WT mice, expressed OX40L (Fig. 1
). Two of the three transgenic lines
(OX40L-Tg1 and OX40L-Tg2) exhibited appreciable expression of OX40L in
splenic T cells, whereas the OX40L-Tg3 line showed comparable OX40L
expression to WT splenic T cells (Fig. 1). Furthermore, the level of
OX40L expression on OX40L-Tg1 splenic T cells was three times higher
than that on OX40L-Tg2 splenic T cells (Fig. 1). Founders of the
OX40L-Tg mice on the (C57BL/6 x DBA/2)F1
strain developed normally and exhibited no readily detectable
abnormalities. However, when these mice were back-crossed onto the
C57BL/6 strain, we noticed weight loss accompanied with diarrhea in the
OX40L-Tg1 and -Tg2 mice.
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On gross examination of the lymphoid organs of OX40L-Tg1 and
OX40L-Tg2 mice, massive splenomegaly and marked lymphadenopathy were
observed. All other organs appeared normal including the thymus when
compared with WT littermates. We next determined by flow cytometry
whether the OX40L transgene in mice resulted in any intrinsic changes
in the overall composition of the lymphocyte populations in the thymus,
spleen, and lymph nodes. All three OX40L-Tg lines did not display any
apparent abnormality in the numbers or subpopulations of T cells in the
thymus as assessed by CD4+ and
CD8+ expression (data not shown). However, the
total number of lymphocytes in the spleen (Fig. 2A) and lymph nodes (data not
shown) were significantly increased in OX40L-Tg1 and OX40L-Tg2 mice as
compared with the WT littermates. More precisely, a 2-fold increase of
splenic CD4+ T cells but not
CD8+ T cells was detected in these two OX40L-Tg
lines at 7 wk of age (Fig. 2A), while the numbers of splenic
IgM+B220+ B cells in all
the three OX40L-Tg lines were comparable to WT littermates (data not
shown). By analyzing the TCR V usage, no skewing of TCR repertoires
of the splenic CD4+ T cells in both the OX40L-Tg1
and -Tg2 mice were found (data not shown), indicating the absence of
oncogenic features.
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B).
Similarly, this remarkable increase in the memory
CD4+ T cell population was observed in the
OX40L-Tg2 mice; however, this was not evident in the OX40L-Tg3 mice
(data not shown). Conversely, a significant reduction in this
population of CD4+ T cells was evident in the
OX40L-deficient mice as compared with the WT mice (Fig. 2B).
The results thus far reveal that OX40L-Tg mice harbor a markedly
elevated memory T cell subpopulation, illustrating the importance of
OX40/OX40L interaction in the generation or/and maintenance of memory
CD4+ T cells in vivo. Markedly enhanced Ag-specific responses of OX40L-Tg memory CD4+ T cells
To address the mechanism responsible for the elevated phenotypic
memory CD4+ T cell population seen of the
OX40L-Tg1 and -Tg2 mice, we conducted a series of Ag-specific recall
proliferation assays of CD4+ T cells. OX40L-Tg
CD4+ T cells had a markedly enhanced
proliferative recall response to KLH (Fig. 3A), while productions of
IL-2, IFN-, IL-4, and IL-5 were also significantly enhanced when
compared with the WT CD4+ T cells (Fig. 3B). However, secretion of the regulatory cytokine, IL-10,
by OX40L-Tg CD4+ T cells was reduced in relation
to WT CD4+ T cells (Fig. 3B). Next,
mice were administrated with KLH in the absence of adjuvant. As
expected, a limited proliferative response by the
CD4+ T cells derived from the WT mice
administered with either no Ag or soluble KLH was seen (Fig. 3C). In contrast, soluble KLH administration induced an
obvious dose-dependent proliferative response by the
CD4+ T cells derived from the OX40L-Tg mice (Fig. 3C). Furthermore, productions of IL-4, IL-5, IL-10, and
IL-13, but not IFN-, by OX40L-Tg CD4+ T cells
were readily detectable (Fig. 3D), while no marked
production of these cytokines in the WT CD4+ T
cells were observed (Fig. 3D). These findings indicate that
OX40L-Tg mice are able to generate highly functional Ag-specific memory
CD4+ T cell responses even in the absence of
adjuvant.
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In view of the extraordinary elevated number and functional
capacity of the CD4+ memory T cells in the
OX40L-Tg mice, we examined the in vivo clonal T cell deletion of these
mice during activation-induced cell death (AICD), a well-known
mechanism of peripheral T cell tolerance. Because clonal T cell
deletion induced by superantigen, such as S. aureus
enterotoxin A and SEB, mimics T cell AICD (44, 45), we
examined whether SEB administered to OX40L-Tg mice would induce the
deletion of the peripheral V8+ T cell
repertoire. Interestingly, the
V8+CD4+ T cell
population in the OX40L-Tg mice remained markedly elevated up to at
least 14 days after the SEB injection (Fig. 4A), while the WT
V8+CD4+ T cell
population, despite peaking on day-2 postinjection, promptly decreased
by day 7 (Fig. 4A). Control
V6+CD4+ peripheral T
cell populations from OX40L-Tg and WT CD4+ T
cells, TCRs of which are not recognized by SEB, remained unchanged
(Fig. 4B). V8+ T cell deletion
induced by SEB treatment is thus defective in OX40L-Tg mice, suggesting
that constitutive OX40/OX40L interactions prevents clonal deletion of
CD4+ T cells during AICD.
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We next determined the levels of all the Ig isotypes, and of
various Th1 and Th2 cytokines in the sera of OX40L-Tg1 mice. OX40L-Tg1
mice apparently had markedly elevated serum levels of all Ig classes
except IgG3 when compared with WT littermates (Fig. 5A). Notably, anti-DNA Abs
to ssDNA and dsDNA were elevated in the sera of OX40L-Tg1 mice (Fig. 5B). These data suggest that the OX40L-Tg1 mice develop
polyclonal activation of B cells accompanied with production of
autoantibodies specific for DNA. We next attempted to determine whether
the serum levels of particular cytokines that affect Ig secretion of B
cells were altered. Serum levels of IL-5 and IL-13 were four and seven
times higher, respectively, in the OX40L-Tg1 mice in comparison to the
WT littermates (Fig. 5C). In contrast, the cytokine
levels of IL-2, IL-4, IL-10, and IFN- were undetectable in the sera
of both the OX40L-Tg1 mice and WT littermates (data not shown). Similar
results to the OX40L-Tg1 mice were also seen among the OX40L-Tg2 mice
(data not shown).
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In view of the weight loss, symptoms of diarrhea, and the detection of elevated serum autoantibody levels in both OX40L-Tg1 and OX40L-Tg2 C57BL/6 mice, we conducted histopathological analyses of a broad spectrum of tissues in these mice. Cervical lymph node sections from the OX40L-Tg1 mice showed increased numbers of plasma cells when compared with WT mice (data not shown). Furthermore, numerous Mott cells containing Russell bodies, intracellular acidophilic deposits often found in mice with autoimmune diseases (46), were visible in sections derived from the OX40L-Tg1 mice (data not shown).
A remarkable appearance of inflammatory cells, consisting of
lymphocytes, neutrophils, and macrophages were seen in the alveolar
septa of lung sections obtained from OX40L-Tg1 mice (Fig. 6, B and D). These
features were consistent with an acute interstitial pneumonia
presentation. Infiltration of lymphocytes also into the peribronchiolar
regions in OX40L-Tg1 lung sections (Fig. 6B) appeared to
closely resemble bronchiolitis. These lung histological features were
consistently absent in the WT littermates (Fig. 6, A and
C).
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F), all
of which were visibly absent in the WT colon sections (Fig. 6E). Further magnification of the OX40L-Tg1 colon sections
revealed the presence of a mixed inflammatory cell infiltrate in the
submucosal regions, consisting of lymphocytes, plasma cells, and
neutrophilic granulocytes (Fig. 6G). In the mucosal
epithelium, typical crypt abscesses were occasionally identified in the
OX40L-Tg1 colon sections (Fig. 6H). Taken together, this
presentation appears to be reminiscent of IBD.
All these histopathological findings appeared 3 mo postnatal in the
OX40L-Tg1 and OX40L-Tg2 and not the OX40L-Tg3 line (Table I). This was a significant finding since
OX40L-Tg3 mice have marked expression of OX40L only in thymic and not
splenic tissues (Fig. 1). Therefore, it is likely that overexpression
of OX40L in the periphery may mediate the pathogenesis of these
inflammatory diseases. Additional results show that the development of
interstitial pneumonia and IBD is age-dependent with the incidence of
the diseases increasing with age (Table I). Other tissue sections
obtained from all the three OX40L-Tg lines, including heart, lung,
aorta, liver, pancreas, submandibular glands, stomach, small
intestines, tibial bones, kidneys, and ankle joints were
histologically normal (data not shown). Furthermore, all three
OX40L-Tg lines back-crossed onto the BALB/c background up to at least
20 mo of age, presented with no symptoms of disease or histological
abnormalities in lung or colonic tissues (Table I), indicating the
genetic background specificity in disease development.
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Organ-specific inflammatory diseases in RAG2-deficient mice reconstituted with OX40L-Tg CD4+ T cells
Immunohistochemical analysis of the infiltrating lymphocytes in
both the peribronchiolar regions of the lung and the intestinal lamina
propria of the OX40L-Tg1 mice had a CD4+
phenotype (data not shown), demonstrating the possible participation of
CD4+ T cells in the pathogenesis of these
organ-specific autoimmune-like diseases. To determine whether OX40L-Tg
CD4+ T cells mediate the pathogenesis of the
diseases seen in the OX40L-Tg mice, we conducted a series of transfer
experiments, in which CD4+ T cells derived from
OX40L-Tg1 or WT mice were transferred i.v. into C57BL/6 RAG2-deficient
mice. All the reconstituted RAG2-deficient mice displayed signs of
sickness that included wasting and diarrhea 8 days after inoculation of
OX40L-Tg1 CD4+ T cells (Fig. 7A and data not shown).
Between 2 and 5 wk posttransfer, lung histological sections revealed
inflammatory features consistent with severe interstitial pneumonia
(Fig. 7C), while colon sections showed massive infiltration
of lymphocytes in the intestinal lamina propria (Fig. 7E).
These histological features were reproduced in RAG2-deficient mice
reconstituted with splenic CD4+ T cells derived
from OX40L-Tg2 mice (Table I). In contrast, RAG2-deficient mice
inoculated with CD4+ T cells from the WT mice had
no symptoms of disease (Fig. 7A and data not shown) or
histological abnormalities in lung or colon tissue sections (Table I
and Fig. 7, D and F). Interestingly,
administration of an inhibitory anti-OX40L mAb, MGP34, along with
CD4+ T cells from OX40L-Tg1 mice into
RAG2-deficient mice completely prevented the development of the
diseases (Table I, Fig. 7, G and H). These
results not only demonstrate that OX40L-Tg CD4+ T
cells are the responsible pathogenic effector cells in disease
generation, but highlight the critical involvement of OX40/OX40L
interaction in directly mediating the pathogenesis of these
diseases.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OX40 has been reported to be expressed on autoreactive or effector T
cells in patients with autoimmune diseases (34, 36, 40)
and inflammatory diseases linked to immune disorders
(37, 38, 39). The OX40/OX40L system may thus play a potential
key role in the immune regulation of various autoimmune diseases. One
mechanism to limit autoimmunity is by AICD, which has been considered
to limit accumulation of autoantigen-specific T cells
(50). Although a previous report demonstrated that
treatment with an agonistic anti-OX40 mAb alone was not able to
prevent S. aureus enterotoxin A-induced AICD
(21), AICD triggered by SEB administration was markedly
impaired in OX40L-Tg mice (Fig. 4A). Because AICD plays an
important role in regulating autoimmunity, defective AICD seen in
OX40L-Tg mice may cause a marked elevation of effector memory
CD4+ T cells and lead to autoimmune-like disease
development. In addition, a recent report suggested a possible
involvement of OX40 signaling in breaking peripheral
CD4+ T cell tolerance (25). However,
to further clarify the plausible association between the defective
AICD, probably resulting in a break in peripheral tolerance and the
autoimmune-like diseases seen in the OX40L-Tg mice, studies using
Ag-specific T cells derived from a TCR transgenic mouse intercrossed to
an OX40L-Tg mouse are required.
The spontaneous development of autoimmune-like diseases of the lung and colon in OX40L-Tg mice may provide us with the first evidence demonstrating the direct link of OX40 signaling to the development of immune disorder-associated diseases. This association is strongly supported by our results showing the effectiveness of an inhibitory anti-OX40L mAb in completely preventing these diseases in syngenic RAG2-deficient mice reconstituted with pathogenic OX40L-Tg CD4+ T cells. Although elevated serum autoantibody levels were seen in the OX40L-Tg mice, it is clear that B cells are not essential in the pathogenesis of interstitial pneumonia or IBD, since the reconstituted RAG2-deficient mice which lack B cells developed these diseases. However, this finding does not rule out the possibility that autoantibodies might lead to autoimmune manifestations in OX40L-Tg mice.
The Th2-biased responses observed in OX40L-Tg mice may be compatible
with previous in vitro studies demonstrating that OX40-cross-linking on
T cells upon Ag- or TCR-stimulation induces enhanced IL-4 production,
but not IFN- (51, 52, 53). Interestingly, when immunizing
Ag into OX40L-Tg mice in the absence of adjuvant, only Th2 cytokines
were produced by CD4+ T cells (Fig. 3D), although Ag immunized with adjuvant induced higher
cytokine production in both Th1 and Th2 responses in OX40L-Tg mice
(Fig. 3B). In addition, OX40L-Tg mice exhibited higher serum
levels of IL-5 and IL-13 (Fig. 5C). These results
clearly indicate that constitutive OX40/OX40L interaction, probably
leading to excessive OX40 signaling in T cells, induces Th2 responses
in vivo. In contrast, transgenic mice for CD70 (CD27 ligand), which is
also a T cell costimulatory molecule belonging to TNF family members,
have reportedly demonstrated Th1-dominant phenotypes, such as high
IFN- production (54), suggesting distinct costimulatory
functions on Th responses of TNFR family molecules on T cells.
Pulmonary abnormalities and ulcerative colitis are found in patients with HTLV-I-associated diseases (55, 56, 57). Expression of OX40L, which was initially described on HTLV-I-infected human T cell lines (7, 8), was detected on activated T cells (9, 10) and long-term cultured cytotoxic T cell clones (11). The interaction between OX40 and OX40L via T cell-T cell interactions may possibly have implications in the pathogenesis of these HTLV-I-associated diseases.
The onset of most human autoimmune diseases is apparently dependent on some specific genetic backgrounds such as HLA, sex-chromosomal genes, etc. The observation that the autoimmune-like diseases seen in the OX40L-Tg mice are mouse strain-dependent leads us to the conclusion that further studies by chromosomal linkage analysis of possible causative genes using resistant and susceptible strains will be required. OX40L-Tg mice may thus be a useful tool in evaluating the pathogenesis of interstitial pneumonia and IBD.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Naoto Ishii, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aobu-ku, Sendai 980-8575, Japan. E-mail address: ishiin{at}mail.cc.tohoku.ac.jp
3 Abbreviations used in this paper: OX40L, OX40 ligand; OX40L-Tg, OX40L-transgenic; IBD, inflammatory bowel disease; RAG, recombination-activating gene; KLH, keyhole limpet hemocyanin; SEB, S. aureus enterotoxin B; HTLV, human T cell leukemia virus; CD62L, L-selectin; AICD, activation-induced cell death; WT, wild type.
Received for publication June 14, 2002. Accepted for publication August 12, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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47/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patient with inflammatory bowel disease. Gut 45:856.8+CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature 349:245.[Medline]
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 A. D. Weinberg, D. E. Evans, C. Thalhofer, T. Shi, and R. A. Prell The generation of T cell memory: a review describing the molecular and cellular events following OX40 (CD134) engagement J. Leukoc. Biol., June 1, 2004; 75(6): 962 - 972. [Abstract] [Full Text] [PDF]
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S. K. Lathrop, C. A. Huddleston, P. A. Dullforce, M. J. Montfort, A. D. Weinberg, and D. C. Parker A Signal through OX40 (CD134) Allows Anergic, Autoreactive T Cells to Acquire Effector Cell Functions J. Immunol., June 1, 2004; 172(11): 6735 - 6743. [Abstract] [Full Text] [PDF]
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I. Takeda, S. Ine, N. Killeen, L. C. Ndhlovu, K. Murata, S. Satomi, K. Sugamura, and N. Ishii Distinct Roles for the OX40-OX40 Ligand Interaction in Regulatory and Nonregulatory T Cells J. Immunol., March 15, 2004; 172(6): 3580 - 3589. [Abstract] [Full Text] [PDF]
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G. Demirci, F. Amanullah, R. Kewalaramani, H. Yagita, T. B. Strom, M. H. Sayegh, and X. C. Li Critical Role of OX40 in CD28 and CD154-Independent Rejection J. Immunol., February 1, 2004; 172(3): 1691 - 1698. [Abstract] [Full Text] [PDF]
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), OX40L-Tg2 (n = 5,
), OX40L-Tg3 (n = 5, 
), and WT mice
(n = 5, 
) were counted and stained with
PE-conjugated anti-CD4-mAb and FITC-conjugated anti-CD8-mAb.
*, p < 0.05; **, p <
0.005; cf WT mice per group as determined by Student’s
t test. B, Populations of splenic memory
(CD62LlowCD44high) CD4+ T cells in
OX40L-Tg1 (n = 5, •), OX40L-deficient
(n = 4, 
) were evaluated. Splenocytes from each mouse were counted and
stained with CD62L-FITC, CD44-CyChrome, and CD4-PE at the indicated
days after birth. *, p < 0.05; **,
p < 0.005; cf WT mice.
