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Immunology Division, Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production. These
results indicate that ICOS/B7h counterreceptors likely function in vivo
to enhance secondary responses by CD8+ T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, a homolog of CD28 was identified in a screen for activation
Ags on T cells (6). This molecule, ICOS, enhances
proliferation of T cells as well as the production of several cytokines
(IL-4, IL-5, GM-CSF, TNF-
, IFN-, and IL-10). ICOS is expressed
only on activated T cells and does not interact with B7.1 or B7.2.
Instead it binds to B7h (B7RP-1, GL-50, ICOSL), a recently identified
molecule with homology to B7.1 and B7.2 (7, 8, 9, 10). B7h is
expressed on B cells, macrophages, and dendritic cells and has been
shown to provide costimulation in vitro and enhance B cell/T cell
proliferation and differentiation in vivo (7, 8, 9, 11). In
contrast to CD28 costimulation, ICOS may be providing costimulatory
signals to previously activated T cells based on its inducible
expression shortly after T cell activation.
ICOS is expressed on both CD4+ and CD8+ T cells and appears to enhance T cell-dependent Ab responses and cytokine production from CD4+ cells (6, 8, 12). However, the potential function of ICOS expressed on CD8+ T cells in the generation of MHC class I-specific CTL is less well understood. Activation of effective CD8+ responses does not always require exogenous help from CD4+ Th cells, which may only be required when TCR affinity is low (13, 14). CD8+ T cells can be stimulated to proliferate and generate CTL responses to alloantigens in the absence of CD4+ Th cells (15, 16, 17). It has been demonstrated that costimulation of naive CD8+ T cells through CD28 allows for the induction of CTL responses without exogenous help (18).
We previously reported that transcription of the B7h gene
could be induced in 3T3 and embryonic fibroblast cell lines treated
with TNF- and that B7h was basally expressed in several nonlymphoid
tissues of healthy mice (7). To explore the potential in
vivo significance of these observations, we used a murine tumor model
to examine the consequences of B7h expression on cells in nonlymphoid
tissues. Ectopic expression of B7h resulted in enhanced tumor rejection
that could be mediated by CD8+ T cells in the
absence of CD4+ T cells. Although B7h was able to
augment anti-tumor responses by both priming responses of naive T
cells and by augmenting secondary recall responses of
CD8+ T cells, the enhancement of recall responses
by B7h was striking. To examine why B7h was particularly effective in
enhancing recall responses, we examined different effector responses of
CD8+ T cells in vitro using transgenic T cells,
where the antigenic specificity of responder cells is well defined. We
observed an in vitro correlate in the ability of B7h to costimulate
cytokine production from rechallenged CD8+ T
cells but not naive CD8+ T cells. These data
suggest that ICOS/B7h interactions may play a significant role in
regulating secondary cytotoxic T cell responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six-week-old female BALB/c nude mice and A/J mice (H-2Kk, I-Ak, I-Ek, and Dd) were obtained from Simonsen (Gilroy, CA) and The Jackson Laboratory (Bar Harbor, ME), respectively. 2C TCR-transgenic mice in the C57BL/6 background were obtained from a colony maintained at our institution. All mice were used within 2 mo of receipt in accordance with the animal use guidelines of our institution.
Cells
P815 mastocytoma cells (H-2d, MHC class
II-) were cultured in RPMI 1640 containing
complete medium (10% FCS, 50 µM 2
-ME, 2 mM
L-glutamine, 100 U/ml penicillin, and 100 µg/ml
streptomycin). The chemically induced fibrosarcoma cell line Sa1N
(H-2Kk, I-Ak,
I-Ek, Dd) (19)
and the human kidney cell lines 293T and BOSC23 were cultured in DMEM
supplemented with complete medium.
cDNAs and plasmids
The B7h-Ig version used in this paper is modified from our original paper (7). A myc-tagged version was created by subcloning a KpnI-BamHI B7h insert from our original B7h-Ig and a BamHI-XhoI insert containing the CH2-CH3 domains of mouse IgG1 that was generated by PCR using the following oligonucleotides: 5'-GCGGATCCAGTGCCCAGGATTGTGGT-3' and 5'-GGCCTCGAGTTTACCAGGAGAGTGGGA-3'. Both inserts were ligated in-frame in a trimolecular reaction into the pcDNA4-myc-his vector (Invitrogen, San Diego, CA) and transfected into 293T cells for protein expression.
Generation of Sa1N and P815 clones
Because Sa1N cells are highly immunogenic, introduction of green
fluorescence protein (GFP)3 as a
marker did not alter the growth kinetics of GFP-expressing tumors in
comparison to wild-type tumors in syngeneic mice. We observed no
difference in growth of the four control Sa1N clones expressing GFP
over wild-type Sa1N tumors in A/J and nude mice (data not shown).
Consequently, all Sa1N and P815 tumors clones were generated using a
GFP marker to facilitate cloning. A B7h-GFP protein, previously
characterized as functionally equivalent to wild-type B7h, was
generated by PCR cloning the B7h cDNA into the pEGFP-N3 mammalian
expression vector (Clontech Laboratories, Palo Alto, CA) and then
subcloned into the SalI-NotI sites of a murine stem cell
virus (MSCV) retroviral vector. A murine B7.2 cDNA was cloned into a
MSCV-internal ribosomal entry sequence (IRES)-GFP retroviral vector
using an IRES GFP marker (20). Control clones were
generated in parallel using cells transduced with empty MSCV-IRES-GFP
retroviral vector. Flow cytometric analysis of GFP expression was
equivalent (within a 3-fold range of mean fluorescence over background)
in all Sa1N clones tested, consistent with the comparable staining
observed with an anti-B7h mAb (22D7) for the B7h-Sa1N clones (see
Fig. 1
A) and with an anti-B7.2 mAb (clone GL1;
PharMingen, San Diego, CA; data not shown) for the B7.2-Sa1N
clone used in Fig. 2. Flow cytometric analysis of GFP
expression on B7h- and B7.2-transduced P815 clones was also within a
3-fold range of mean fluorescence over background. High-titer
helper-free retroviral stocks were produced as previously described
(7). For the generation of clones, 24 h following
infection cells were aliquoted into 96-well plates at 0.5 cell/well.
GFP-positive clones were visible by fluorescence microscopy after 2–3
wk of culture. At that time, cells from GFP-positive wells were
replated at a concentration of 0.5 cell/well, and positives were
expanded and tested for expression.
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All primary tumor inoculations were performed by injecting 5 x 105 cells s.c. into the left flank of A/J or BALB/c nude mice. Vernier calipers were used to measure the tumors in two dimensions according to previously established protocols (21, 22). A minimum of four mice was used for each experimental group, and tumor growth was monitored in individually identified mice. All contralateral or secondary injections were made by injecting 5 x 105 cells s.c. into the right flank. For all i.p. immunizations, 2 x 106 irradiated cells were used.
Antibodies
A mAb to B7h (22D7) was generated by immunization of Syrian
hamsters with Chinese hamster ovary cells expressing B7h. For flow
cytometric analysis (Fig. 1
A) an anti-hamster IgG PE Ab
(Caltag, South San Francisco, CA) was used as a second-step reagent.
Hybridomas GK1.5 (anti-CD4) and 2.43 (anti-CD8) were obtained
from American Type Culture Collection (Manassas, VA) and were
maintained in RPMI 1640 supplemented with complete medium. GK1.5 and
2.43 cells were used to generate ascites in BALB/c nude mice. Ab
production was verified by the use of ascites in flow cytometry and
quantified by Western blot using an anti-Rat HRP Ab (Caltag) for
detection and a rat IgG Ab (Sigma, St. Louis, MO) as a standard. An
anti-myc Ab (9E10) was obtained from Santa Cruz Biotechnology
(Santa Cruz, CA) and was used in flow cytometry to detect positive
B7h-Ig binding.
In Vivo T cell depletion
CD4+ and CD8+ T cells were depleted from A/J mice by i.p. injection of ascites equivalent to 0.1 mg GK1.5 or 0.2 mg 2.43, respectively, on three instances 1 wk before s.c. injection of tumor. Control mice were injected with the same dose of purified rat IgG (Sigma). Throughout the experiment, two weekly injections of the same dose were administered i.p. to maintain the depletions. Before the tumor experiment was initiated, one spleen was harvested from each group, and depletion of the relevant subset was verified by flow cytometry with a separate anti-CD4 Ab or anti-CD8 Ab, which are not blocked by the depleting GK1.5 and 2.43 Abs. All mice tested in these studies exhibited >98% depletion of the appropriate T cell subset. For transfer experiments, naive mice were depleted of CD4+ T cells by three injections of the GK1.5 Ab before immunization with 2 x 106 irradiated Sa1N tumor cells. Four injections of the GK1.5 Ab were given in the 2 wk following immunization. Animals were sacrificed, and lymph node T cells were isolated, purified, and transferred. The percentage of transferred CD8+ T cells was >96%.
Cell proliferation and cytokine assays
Lymph node or in vitro expanded CD8+ T
cells were purified as previously described with the inclusion of GK1.5
(anti-CD4) to the complement reaction (7). Final
percentages of CD8+ T cells for primary and
rechallenge experiments were 97 and 99%, respectively. Purified cells
were labeled with CFSE (Molecular Probes, Eugene, OR) according to the
supplier’s protocol. Following CFSE labeling,
CD8+ T cells (8 x
105) were incubated with irradiated control, B7h,
or B7.2 clones (4 x 106) in flat-bottom
plates (24-well) and analyzed by flow cytometry on day 5 (rechallenge)
or day 7 (primary). Supernatants from the in vitro proliferation
experiments were collected at 24 h of culture and assayed for the
presence of cytokines by sandwich ELISA. Naive T cells were checked for
absence of expression activation markers including CD69 and CD25. For
detection of IL-10 in supernatants we used an IL-10 ELISA kit from
PharMingen. Abs for the IL-4 and IFN- ELISAs were gifts from K.
M. Murphy and R. D. Schreiber (Washington University Medical
School, St. Louis, MO). Abs for the IL-2 ELISAs were gifts from J.
P. Allison (University of California, Berkeley, CA). All samples,
including controls, were assayed in triplicate.
Generation of cytotoxic T cells and cytolytic assays
Responder splenocytes from 2C TCR transgenic mice were cocultured with irradiated stimulator BALB/c splenocytes in complete medium at 37°C for 5 days at a 2:1 stimulator-responder ratio. 51Cr-labeled P815 target clones were incubated with the expanded 2C T cells in round-bottom 96-well plates at different ratios. 51Cr-containing supernatants were counted after 6 h. All samples, including controls, were assayed in triplicate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the potential role of B7h expression observed in nonlymphoid tissues, we used a well-established murine tumor model that allowed us to quantitate the immune response elicited by B7h by measuring tumor growth. The murine fibrosarcoma cell line Sa1N expresses MHC class I, but does not express MHC class II, and is negative for B7.1, B7.2, and B7h expression (Ref. 19 , data not shown). Sa1N is a highly immunogenic tumor that stimulates an ineffective, but specific, immune response in vivo (23). Because of its high degree of immunogenicity, Sa1N tumor growth is unaffected by the intracellular expression of marker proteins like GFP. In contrast, surface expression of B7.1 on Sa1N cells has been shown in several previous studies to significantly enhance anti-tumor responses resulting in rapid tumor rejection (21, 24).
Immune responses to Sa1N cells expressing B7h were evaluated by
monitoring tumor growth of B7h-expressing Sa1N cells (B7h-Sa1N) in
comparison to control Sa1N cells (control Sa1N). Individual clones of
Sa1N cells expressing B7h and control clones were generated by
retroviral transduction (Fig. 1A). Tumor growth was assessed
every 2–3 days following s.c. injection into syngeneic A/J mice
throughout the duration of the experiment or until tumors became
ulcerated (Fig. 1B). Progressive growth of control Sa1N
tumors was observed in all four clones tested. However, ectopic B7h
expression resulted in rejection of Sa1N tumors in all four
clones tested. B7h-Sa1N clones initially grew equivalently to control
clones for the first 11 days, but between days 11 and 13 became static
in comparison to control Sa1N tumors. By day 20, most B7h-Sa1N tumors
had completely regressed. Residual B7h-Sa1N tumors remaining in mice at
day 20 either remained static or continued to regress as long as mice
were maintained (up to 3 mo). The ability of B7h to augment
anti-tumor responses was dependent upon host T cell responses,
as all of the clones grew progressively in nude mice. Equivalent growth
in nude mice was observed for the B7h-Sa1N (number 4) and control Sa1N
(number 4) clones used in subsequent experiments (Fig. 1C).
To determine which subset(s) of T cells were involved in B7h
enhancement of immune responses to tumors, A/J mice were depleted of
either CD4+ or CD8+ T cells
before inoculation with B7h-Sa1N cells (Fig. 1D).
Effectiveness of depletions with specific and control Abs was confirmed
at the initiation and twice during the experiment by flow cytometric
analysis. In each case, >98% depletion of the respective T cell
subset was observed (data not shown). A/J mice depleted of
CD8+ T cells were unable to respond to B7h-Sa1N
cells, and tumors grew progressively for the entirety of the
experiment. In contrast, mice depleted of CD4+ T
cells eliminated B7h-Sa1N tumors with only slightly delayed kinetics in
comparison to mice treated with a control Ab. These data indicate that
CD8+ T cells were capable of mediating rejection
of B7h-Sa1N tumors in the absence of CD4+ T
cells.
B7h enhances priming by live tumor cells of responses of naive T cells
We next sought to address whether B7h was effective in costimulating tumor rejection by acting early in the response to enhance priming of naive T cells or by acting later in the response to enhance responses of T cells that had been primed. Emerging data for regulation of CD4+ T cell responses suggest that ICOS/B7h interactions play a more significant role in regulating secondary immune responses than in primary responses where CD28 interactions with B7.1 and B7.2 appear more critical (12). Because rejection of B7h-Sa1N tumors could be mediated entirely by CD8+ T cells, we used the Sa1N tumor model to examine whether an analogous difference existed in the ability of B7h to regulate primary and recall responses of CD8+ T cells.
To assess the effectiveness of B7h early in the response, different
s.c. tumors were allowed to grow for 3 days before a second control
tumor was introduced at a contralateral site (Fig. 2A). Growth of this second
tumor was measured and used to assess the effectiveness of priming by
B7h- or B7.2-expressing clones in comparison to priming by control
clones or no priming. Under these conditions, control clones were only
modestly effective at priming responses. In contrast, s.c. priming with
a B7.2-Sa1N clone resulted in enhanced rejection of control Sa1N
tumors. Subcutaneous priming with B7h-Sa1N clones also inhibited growth
of control Sa1N tumors, but somewhat less effectively than a B7.2-Sa1N
clone. These differences in priming by live tumor cells were unlikely
to have resulted from differences in antigenicity of clones, because
all clones prevented growth of a second tumor under conditions where
cross-presentation of tumor Ags by host APCs was maximized by i.p.
immunization with irradiated cells (Fig. 2B). These results
indicate that B7h can act early in an in vivo response to directly
prime responses of naive T cells.
B7h markedly augments recall responses of CD8+ T cells
We next examined the ability of B7h to augment anti-tumor activity in secondary recall responses of T cells. Rejection of B7h-Sa1N tumors resulted in strong protective host immunity to rechallenge with Sa1N cells. Mice that had rejected B7h-Sa1N tumors and were rested for at least 4 wk showed no tumor growth upon rechallenge with either control Sa1N or B7h-Sa1N cells introduced at a second s.c. site (data not shown). This vigorous secondary rejection in previously immunized mice led us to use an adoptive transfer approach to examine the importance of B7h in augmenting secondary anti-tumor responses.
In these adoptive transfer experiments, T cells from rested A/J mice
that had previously rejected B7h-Sa1N tumors were adoptively
transferred into A/J mice with pre-existing contralateral control Sa1N
and B7h-Sa1N tumors (Fig. 3). Growth of
these two tumors was then monitored to assess the ability of B7h to
modulate secondary responses of T cells. The B7h-Sa1N and control Sa1N
clones used in these experiments grew equivalently in both nude mice
(Fig. 1C) and in A/J mice for the first 11 days (Fig. 3A). Consistent with our previous observation that rejection
of the B7h-Sa1N clone conferred vigorous protective immunity against
rechallenge with either clone, i.p. immunization with irradiated cells
from both the B7h-Sa1N or control Sa1N clones resulted in an absence of
tumor growth upon rechallenge with either clone (data not shown). Thus,
both clones maintained antigenic cross-reactivity, and transferred T
cells were capable of recall responses against both clones.
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A). In marked contrast, adoptive transfer of
106 or 107 T cells from
immunized mice resulted in rapid and efficient rejection of B7h-Sa1N
tumors, whereas little or no impairment in growth of contralateral
control tumors was observed. Even at the lowest dose of
105 transferred T cells, B7h-Sa1N tumors were
still rejected. Thus, B7h was extremely rapid and efficient in
mobilizing anti-tumor responses in secondary recall responses. The
magnitude of this enhancement of recall responses by B7h is highlighted
by the inability of the highest dose of transferred T cells to alter
growth of the contralateral control tumor.
To confirm that these rapid recall responses were mediated by
CD8+ T cells, we also transferred recall
responder CD8+ T cells, purified from mice
depleted of CD4+ T cells that were immunized with
irradiated control-Sa1N cells (Fig. 3B). Adoptive transfer
of 107 recall responder
CD8+ T cells resulted in significant growth
inhibition of both control-Sa1N and B7h-Sa1N tumors, although B7h-Sa1N
tumors were still ablated with much greater efficiency. The growth
inhibition of control-Sa1N tumors observed in this experiment likely
reflects the increased number of cytolytic effectors in transferred
CD8+ T cells that result from i.p. immunization
(see Fig. 2).
These in vivo experiments suggested that B7h was effective in augmenting anti-tumor responses by CD8+ T cells in both primary and secondary recall responses, but that enhancement of recall responses by B7h was particularly effective. To examine why B7h was particularly efficacious in enhancing recall responses, we examined different responses of CD8+ T cells in vitro using transgenic T cells, where the antigenic specificity of responder T cells can be well controlled. For these studies, we used transgenic 2C TCR T cells and P815 target cells that expressed the Ld alloantigen (25). Individual clones of P815 cells were generated that were transduced with retroviral vector alone (control clones), a vector expressing B7h (B7h clones), or a vector expressing B7.2 (B7.2 clones).
B7h costimulates in vitro responses of CD8+ T cells
Because of the rapidity of secondary responses to B7h-expressing
tumors, we first examined the ability of B7h to enhance lytic effector
function of CD8+ T cells (Fig. 4). Expression of B7.1 or B7.2 by target
cells has previously been shown to be insignificant for effector
function of CTL (26). 2C T cells from MLC were assayed for
lytic activity against control, B7h, or B7.2 target cells. No enhanced
lysis of B7h target cells was observed at multiple E:T ratios. These
results indicate that B7h expression on target cells, like B7.1 or
B7.2, did not augment cytolytic activity of activated
CD8+ cells.
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A). Previous
studies have shown that B7h interacts with the cell-surface receptor
ICOS that is not expressed on naive T cells but is induced upon T cell
activation (8, 9, 10). Kinetics of surface ICOS expression
and other potential B7h counterreceptors on activated
CD8+ T cells were examined by flow cytometry
using a B7h-Ig fusion protein that binds ICOS (Fig. 5A). In
primary MLC of transgenic and irradiated BALB/c splenocytes, a large
fraction of CD8+ 2C T cells stained positively
with B7h-Ig by 20 h. By 44 h, all CD8+
T cells were positive, and staining was maximal. Staining with B7h-Ig
was maintained for at least 6 days, but by day 8 had become
undetectable in resting cells. When these resting
CD8+ T cells were rechallenged with BALB/c
stimulators, the entire population of CD8+ T
cells shifted in staining with B7h-Ig by 20 h, suggesting that
up-regulation of ICOS was somewhat more rapid in rechallenged cells
than in naive cells. Surprisingly, the staining observed with B7h-Ig in
rechallenged CD8+ T cells did not reach the
levels or duration seen in a primary MLC.
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B). Purified CD8+ T cells were
labeled with CFSE and cocultured with control, B7h, or B7.2 clones.
Because proliferative responses of CD8+ T cells
from naive mice were weaker than responses of previously activated
cells, cells were assayed by flow cytometry at day 7 for primary
responses, and at day 5 for rechallenge responses. In responses of both
naive and rechallenged CD8+ T cells, B7h clones
enhanced proliferation of CD8+ T cells in
comparison to control clones, although the enhancement of proliferation
was somewhat less effective than B7.2 clones with respect to both the
fraction of cells proliferating and number of cellular divisions. Thus,
ectopic B7h expression costimulated in vitro proliferation of both
naive and rechallenged CD8+ T cells.
Although proliferative responses were similar between naive and
rechallenged cells, B7h clones costimulated differential amounts of
cytokine production from naive and rechallenged
CD8+ T cells (Fig. 5C). For both naive
and rechallenged cells, little IL-10 or IL-4 was elicited in cultures
costimulated with either B7h or B7.2 clones. In rechallenged cells
stimulated by B7h clones, levels of IL-2 and IFN- were elicited that
were comparable to the levels produced by cells stimulated with B7.2
clones. In contrast, levels of IL-2 and IFN- from naive cells
stimulated by B7h clones were significantly less than the cytokine
levels produced by cells stimulated with B7.2 clones, and, instead,
were comparable to levels produced from control clones. These data
suggest that B7h was more effective in costimulating IL-2 and IFN-
production from rechallenged CD8+ T cells than
from naive CD8+ T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, but not IL-10 or IL-4, production, from
CD8+ T cells. It is well known that help provided
by CD4+ Th cells can augment a CTL response.
However, sufficient effector CD8+ CTL can also be
generated in the absence of CD4+ T cells
(18). Rejection of B7h-expressing tumors, like
B7.1-expressing tumors (27, 28), was not dependent on
CD4+ T cell help. This ability of B7h to directly
costimulate CD8+ T cells expressing ICOS may be
critical in augmenting anti-tumor responses to Sa1N, particularly
in light of recent studies indicating that ICOS/B7h interactions
preferentially augment Th2 responses (12, 29). Activation
of ICOS in human T cells was originally shown to costimulate production
of the Th2-cytokine IL-10 involved in inhibition of Th1 responses
(6). More recently, ICOS was shown to be important as a
costimulatory receptor for both recently activated cells and for Th2
but not Th1 effector cells (12). A striking feature of costimulation by ICOS/B7h is the emerging data indicating that ICOS/B7h interactions play a more significant role in regulating secondary immune responses than in primary responses where CD28-B7.1 and B7.2 interactions appear more critical. In a model of contact hypersensitivity, activation of ICOS at the time of challenge was found to be significantly more effective in exacerbating contact hypersensitivity than when ICOS was activated at the initial sensitization phase (8). Blockade of ICOS activation was also found to be more potent than blockade of CD28 activation in inhibiting cytokine production from recently activated CD4+ T cells, but not from naive CD4+ cells where CD28 blockade was more critical (12).
Our results with a tumor model suggest that ICOS/B7h interactions are
also more potent in enhancing secondary recall responses of
CD8+ T cells than in primary responses. In
primary responses to tumors, ectopic B7h expression augmented tumor
rejection, but inhibition of tumor growth was observed only after 11
days of tumor growth. However, in secondary responses to tumors,
ectopic B7h expression was highly efficient and rapid in enhancing
tumor rejection by CD8+ T cells. This ability of
B7h to rapidly mobilize tumor rejection in secondary responses did not
appear to result from enhancement of CTL lytic effector function.
Because B7h was found to directly costimulate proliferation of
CD8+ T cells in vitro, it is likely that direct
priming and expansion of CD8+ T cells contributed
to enhanced rejection of B7h-expressing tumors. Consistent with
previous studies demonstrating enhanced cytokine production from
rechallenged over naive T cells (30), we observed that B7h
preferentially costimulated IL-2 and IFN- production from
rechallenged CD8+ T cells over naive cells in
comparison to B7.2, suggesting a potential basis for the effectiveness
of B7h in enhancing in vivo secondary responses.
The ability of ICOS/B7h interactions to enhance anti-tumor
responses of CD8+ T cells to Sa1N suggests that
B7h may also be involved in regulation of CD8+ T
cells in other contexts. However, in a model of lymphocytic
choriomeningitis virus and vesicular stomatitis virus infection where
ICOS regulation was examined, ICOS was shown to regulate
CD4+ responses of Th1 and Th2 subsets, but not
CTL responses (31). Although CTL responses were not found
to be regulated by ICOS, only primary responses, and not secondary
responses, were examined in these viral infection models. It will be of
interest to examine the role of ICOS/B7h in memory
CD8+ T cell responses, particularly given the
observations that B7h is found expressed at low levels in peripheral
tissues of normal mice and can in vitro be induced on fibroblast cell
lines treated with the inflammatory cytokine TNF-
(7).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. William C. Sha, 441 Life Sciences Addition, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200. E-mail address: bsha{at}uclink4.berkeley.edu
3 Abbreviations used in this paper: GFP, green fluorescence protein; MSCV, murine stem cell virus; IRES, internal ribosomal entry sequence.
Received for publication December 13, 2000. Accepted for publication April 23, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Immunity 11:423.[Medline]
interferon promoter elements in naive and memory (effector) CD4 T cells and CD8 T cells. Mol. Cell Biol. 17:199.[Abstract]
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E. C. Logue, S. Bakkour, M. M. Murphy, H. Nolla, and W. C. Sha ICOS-Induced B7h Shedding on B Cells Is Inhibited by TLR7/8 and TLR9 J. Immunol., August 15, 2006; 177(4): 2356 - 2364. [Abstract] [Full Text] [PDF]
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X.-Z. Yu, Y. Liang, R. I. Nurieva, F. Guo, C. Anasetti, and C. Dong Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells. J. Immunol., June 15, 2006; 176(12): 7394 - 7401. [Abstract] [Full Text] [PDF]
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 K. Warnatz, L. Bossaller, U. Salzer, A. Skrabl-Baumgartner, W. Schwinger, M. van der Burg, J. J. M. van Dongen, M. Orlowska-Volk, R. Knoth, A. Durandy, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency Blood, April 15, 2006; 107(8): 3045 - 3052. [Abstract] [Full Text] [PDF]
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 M. Vidric, A. T. Bladt, U. Dianzani, and T. H. Watts Role for Inducible Costimulator in Control of Salmonella enterica Serovar Typhimurium Infection in Mice Infect. Immun., February 1, 2006; 74(2): 1050 - 1061. [Abstract] [Full Text] [PDF]
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M. Vidric, W.-K. Suh, U. Dianzani, T. W. Mak, and T. H. Watts Cooperation between 4-1BB and ICOS in the Immune Response to Influenza Virus Revealed by Studies of CD28/ICOS-Deficient Mice J. Immunol., December 1, 2005; 175(11): 7288 - 7296. [Abstract] [Full Text] [PDF]
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 M. G. Petroff, E. Kharatyan, D. S. Torry, and L. Holets The Immunomodulatory Proteins B7-DC, B7-H2, and B7-H3 Are Differentially Expressed across Gestation in the Human Placenta Am. J. Pathol., August 1, 2005; 167(2): 465 - 473. [Abstract] [Full Text] [PDF]
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M. E. A. T. van Berkel, E. H. R. Schrijver, F. M. A. Hofhuis, A. H. Sharpe, A. J. Coyle, C. P. Broeren, K. Tesselaar, and M. A. Oosterwegel ICOS Contributes to T Cell Expansion in CTLA-4 Deficient Mice J. Immunol., July 1, 2005; 175(1): 182 - 188. [Abstract] [Full Text] [PDF]
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 M. Watanabe, Y. Hara, K. Tanabe, H. Toma, and R. Abe A distinct role for ICOS-mediated co-stimulatory signaling in CD4+ and CD8+ T cell subsets Int. Immunol., March 1, 2005; 17(3): 269 - 278. [Abstract] [Full Text] [PDF]
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C. Mayr, D. Bund, M. Schlee, A. Moosmann, D. M. Kofler, M. Hallek, and C.-M. Wendtner Fibromodulin as a novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (CLL), which allows expansion of specific CD8+ autologous T lymphocytes Blood, February 15, 2005; 105(4): 1566 - 1573. [Abstract] [Full Text] [PDF]
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 B. Saatian, X.-Y. Yu, A. P. Lane, T. Doyle, V. Casolaro, and E. Wm. Spannhake Expression of genes for B7-H3 and other T cell ligands by nasal epithelial cells during differentiation and activation Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L217 - L225. [Abstract] [Full Text] [PDF]
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 J. Schmidt, G. Rakocevic, R. Raju, and M. C. Dalakas Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity Brain, May 1, 2004; 127(5): 1182 - 1190. [Abstract] [Full Text] [PDF]
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S.-C. Wong, E. Oh, C.-H. Ng, and K.-P. Lam Impaired germinal center formation and recall T-cell-dependent immune responses in mice lacking the costimulatory ligand B7-H2 Blood, August 15, 2003; 102(4): 1381 - 1388. [Abstract] [Full Text] [PDF]
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 X. Liu, J. X. Gao, J. Wen, L. Yin, O. Li, T. Zuo, T. F. Gajewski, Y.-X. Fu, P. Zheng, and Y. Liu B7DC/PDL2 Promotes Tumor Immunity by a PD-1-independent Mechanism J. Exp. Med., June 16, 2003; 197(12): 1721 - 1730. [Abstract] [Full Text] [PDF]
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H. Wiendl, M. Mitsdoerffer, D. Schneider, A. Melms, H. Lochmuller, R. Hohlfeld, and M. Weller Muscle fibres and cultured muscle cells express the B7.1/2-related inducible co-stimulatory molecule, ICOSL: implications for the pathogenesis of inflammatory myopathies Brain, May 1, 2003; 126(5): 1026 - 1035. [Abstract] [Full Text] [PDF]
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K. M. Smith, J. M. Brewer, P. Webb, A. J. Coyle, C. Gutierrez-Ramos, and P. Garside Inducible Costimulatory Molecule-B7-Related Protein 1 Interactions Are Important for the Clonal Expansion and B Cell Helper Functions of Naive, Th1, and Th2 T Cells J. Immunol., March 1, 2003; 170(5): 2310 - 2315. [Abstract] [Full Text] [PDF]
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H.-W. Mittrucker, M. Kursar, A. Kohler, D. Yanagihara, S. K. Yoshinaga, and S. H. E. Kaufmann Inducible Costimulator Protein Controls the Protective T Cell Response Against Listeria monocytogenes J. Immunol., November 15, 2002; 169(10): 5813 - 5817. [Abstract] [Full Text] [PDF]
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H. Iwai, Y. Kozono, S. Hirose, H. Akiba, H. Yagita, K. Okumura, H. Kohsaka, N. Miyasaka, and M. Azuma Amelioration of Collagen-Induced Arthritis by Blockade of Inducible Costimulator-B7 Homologous Protein Costimulation J. Immunol., October 15, 2002; 169(8): 4332 - 4339. [Abstract] [Full Text] [PDF]
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K. Ogasawara, S. K. Yoshinaga, and L. L. Lanier Inducible Costimulator Costimulates Cytotoxic Activity and IFN-{gamma} Production in Activated Murine NK Cells J. Immunol., October 1, 2002; 169(7): 3676 - 3685. [Abstract] [Full Text] [PDF]
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E. N. Villegas, L. A. Lieberman, N. Mason, S. L. Blass, V. P. Zediak, R. Peach, T. Horan, S. Yoshinaga, and C. A. Hunter A Role for Inducible Costimulator Protein in the CD28- Independent Mechanism of Resistance to Toxoplasma gondii J. Immunol., July 15, 2002; 169(2): 937 - 943. [Abstract] [Full Text] [PDF]
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L. Liang, E. M. Porter, and W. C. Sha Constitutive Expression of the B7h Ligand for Inducible Costimulator on Naive B Cells Is Extinguished after Activation by Distinct B Cell Receptor and Interleukin 4 Receptor-mediated Pathways and Can Be Rescued by CD40 Signaling J. Exp. Med., July 1, 2002; 196(1): 97 - 108. [Abstract] [Full Text] [PDF]
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 G. Richter, M. Hayden-Ledbetter, M. Irgang, J. A. Ledbetter, J. Westermann, I. Korner, K. Daemen, E. A. Clark, A. Aicher, and A. Pezzutto Tumor Necrosis Factor-alpha Regulates the Expression of Inducible Costimulator Receptor Ligand on CD34+ Progenitor Cells during Differentiation into Antigen Presenting Cells J. Biol. Chem., November 30, 2001; 276(49): 45686 - 45693. [Abstract] [Full Text] [PDF]
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