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*
Department of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; and
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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Abstract |
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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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Accumulating evidence indicates that not only clonal deletion or anergy, but also T cell-mediated control of self-reactive T cells contributes to the maintenance of immunologic self-tolerance (reviewed in Refs. 6, 7). Indeed, depletion of a CD4+ T cell subpopulation defined by an expression level of a particular cell surface molecule leads to spontaneous development of various autoimmune diseases in otherwise normal rodents. For example, removal of CD5high4+, CD45RB/Clow4+, or CD25+4+ T cells, without deliberate immunization with self Ags, produced in mice or rats autoimmune gastritis, thyroiditis, insulin-dependent diabetes, and other autoimmune diseases immunopathologically similar to human counterparts; reconstitution of the eliminated population prevented the autoimmunities (8, 9, 10, 11, 12, 13, 14, 15). This immunoregulatory activity of CD5high or CD45RB/Clow CD4+ T cells can be attributed to CD25+4+ T cells included in the CD5high or CD45RB/Clow 4+ T cell population (13, 16, 17). Recent studies have shown that the CD25+4+ population in normal naive mice is nonproliferative (anergic) to antigenic stimulation in vitro, and, upon stimulation, potently suppresses the activation/proliferation of other CD4+ or CD8+ T cells in an Ag-nonspecific manner through cell to cell interactions on APCs (16, 17). Furthermore, removal of CD25+4+ T cells not only elicits autoimmunity, but also enhances immune responses to non-self Ags such as allogeneic tissue grafts (13). These in vivo and in vitro findings make it likely that removal of the CD25+4+ immunoregulatory T cells may also evoke effective immune responses to autologous tumor cells in vivo and in vitro by activating effector cells of tumor immunity (18, 19).
In this study, we demonstrate that elimination of CD25+ T cells, which constitute 5–10% of peripheral CD4+ T cells in normal mice and humans (13, 20, 21, 22, 23), indeed elicits potent tumor-specific immune responses to syngeneic tumors in vivo and eradicates them. Furthermore, in vitro culture of CD25+4+ T cell-depleted splenic cell suspensions prepared from tumor-unsensitized normal mice leads to spontaneous generation of active NK cells capable of killing a broad spectrum of tumors. Our results indicate that removal of immunoregulatory CD25+4+ T cells can break immunological unresponsiveness to autologous tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones in otherwise nonresponding individuals. This finding is instrumental in devising effective immunotherapy for cancer in humans.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c, BALB/c-nu/nu, C57BL/6 (B6), and C3H/He mice
of 6 wk of age were purchased from Japan SLC (Shizuoka, Japan),
maintained in our animal facility, and treated in accordance with the
institutional guidelines for animal care. IL-2, IL-4, or IFN-
gene
knockout mice (IL-2-/-,
IL-4-/-, and IFN--/-
mice, respectively (3)) were purchased from The Jackson
Laboratory (Bar Harbor, ME) (24, 25, 26). B6-beige
(bg/bg)3 mice
were purchased from Clea Japan (Tokyo, Japan).
Tumor cells
RL
1 (BALB/c-derived radiation leukemia)
(27, 28, 29, 30), B16 (B6-derived melanoma) (31),
X5563 (C3H-derived plasmacytoma) (32), and P815
(DBA/2-derived mastocytoma) were gifts from Drs. E. Nakayama (Okayama
University, Okayama, Japan), H. Fujiwara (Osaka University, Osaka,
Japan), or T. Takahashi (Aichi Cancer Center, Nagoya, Japan).
Monoclonal Abs
FITC- or PE-labeled anti-CD25 (7D4) (33),
anti-CD4 (GK1.5), anti-NK1.1 (2B4), anti-
/ß-TCR
(H57-597), anti-/
-TCR (GL3), anti-CD24 (M1/69), or
anti-CD16 Ab (2.4G2) was purchased from PharMingen (San Diego, CA).
Hybridomas secreting anti-CD4 (RL172.4), anti-CD8 (3.155), or
anti-CD25 (PC61) Ab were purchased from American Type Culture
Collection (Manassas, VA) . For three-color staining,
R-PE-Cy5-conjugated streptavidin (Dako/Japan, Kyoto, Japan) was used as
the secondary reagent for biotinylated Abs. For in vivo injection of
anti-CD25 mAb, PC61 (rat IgG1) (34) was made ascitic
form in SCID mice and purified from the ascites by 40% ammonium
sulfate precipitation twice. Purified rat IgG for control injections
was purchased from Sigma (St. Louis, MO).
Preparation of T cell subpopulations
Spleen cells were depleted of CD4+, CD8+, or CD25+ cells, as previously described (13, 14). Briefly, spleen cells were incubated at 5 x 106/ml for 45 min at 37°C with the culture supernatant of the hybridoma cells secreting anti-CD4 (RL172.4), anti-CD8 (3.155), or anti-CD25 (7D4) Ab, or the mixture of the supernatants, and rabbit complement (C) 1/10 diluted at the final concentration (Cedarlane Laboratories, Ontario, Canada). The treatment was repeated twice. To purify CD4+ T cells, anti-CD8 plus C-treated cells were removed of B cells and adherent cells by panning on anti-mouse Ig-coated dishes, as previously described (13, 14). To purify CD25+CD4+ T cells, BALB/c spleen cells stained with PE-labeled anti-CD4 (H129.19) (PharMingen) and FITC-labeled anti-CD25 (7D4) were sorted by an EPICS ELITE cell sorter (Coulter Electronics, Miami, FL) with >90% purity, as previously described (16).
In vitro culture of lymphocytes and cytotoxicity assay
Spleen cells (5 x 106 cells in 2 ml) were cultured with or without 5 x 105 mitomycin C-treated tumor cells in DMEM containing 10% FCS in 24-well plates (Costar, Cambridge, MA). Five or seven days later, viable cells were harvested and used as effectors in the 51Cr release cytotoxicity assay, in which target cells (1 x 106) were labeled with 3.7 MBq of sodium chromate (DuPont/NEN, Wilmington, DE) for 60 min at 37°C, washed three times, and incubated at 1 x 104 cells/well with various numbers of effector cells in 96-well round-bottom plates (Costar) for 4 or 6 h at 37°C. The mean percentage specific lysis of triplicate culture was calculated from the radioactivity of the supernatants: percent specific lysis = 100 x [(cpm experimental release - cpm spontaneous release)/(cpm maximum release - cpm spontaneous release)]. Spontaneous release from the target cells incubated in medium alone was always <20% of the maximum release obtained by adding 1 N HCl to the labeled target cells.
To examine the activity of anti-CD4 (RL172.4), anti-CD8
(3.155), anti-/ß-TCR (H57-597), or anti-/-TCR Ab
(GL3) to block the tumor killing mediated by cytotoxic cells, these
mAbs as culture supernatants were added to the 4-h
51Cr release assay described above.
In vitro measurement of cell proliferation and IL-2 activity
Spleen cells (5 x 105/well in 96-well flat-bottom plates (Costar)) were cultured for 3 to 10 days, and pulsed with [3H]thymidine (37 kBq/well) (DuPont/NEN) for the last 6 h. IL-2 activity in the culture supernatants was assessed with the CTLL-2 cell line (35). Murine rIL-2 (3.89 x 106 U/mg) was a gift from Shionogi (Osaka, Japan).
To examine blocking of in vitro proliferation with anti-class II MHC Ab, graded concentrations of pan anti-class II MHC mAb CA4 (36) (a gift from Dr. O. Kanagawa, Washington University, St. Louis, MO) were added to the culture of CD25- spleen cells.
Histological and serological assessment of autoimmune disease
Tissues and organs (thyroid, lung, pancreas, stomach, adrenal gland, kidney, ovaries, or testes) were fixed in 10% Formalin and processed for hematoxylin and eosin staining. Gastritis was graded 0 to 2+, depending on macroscopic and histological severity: 0 = the gastric mucosa was histologically intact; 1+ = mild gastritis with histologically evident destruction of parietal cells and cellular infiltration of the gastric mucosa; 2+ = severe destruction of the gastric mucosa accompanying the formation of giant rugae due to compensatory hyperplasia of mucous-secreting cells (see Ref. 8 for the giant rugae) (13, 14). Thyroiditis was also graded 0 to 2+: 0 = the thyroid gland was histologically intact; 1+ = mild thyroiditis with histologically evident destruction of the thyroid follicles and interstitial infiltration of inflammatory cells; 2+ = severe destruction of the thyroid gland accompanying goiter formation (see Ref. 8 for the goiter) (13, 14). The ELISA (using alkaline phosphatase-conjugated secondary Ab and p-nitrophenyl disodium hexahydrate as the substrate) for detecting autoantibodies specific for the gastric parietal cell Ags or mouse thyroglobulins was previously described (13, 14).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine whether elimination of
CD25+4+ cells is able to
elicit primary immune responses to syngeneic tumors, we transferred to
BALB/c athymic nude mice BALB/c splenic cell suspensions depleted of
CD25+ cells (hereafter designated to be
CD25- cells (see the insets in Fig. 1
A for cytofluorometric
profiles)), and then, on the same day, s.c. transplanted BALB/c-derived
RL1 leukemia cells (Fig. 1A). In the majority of mice,
the tumors first grew and then regressed within 1 mo, allowing the
hosts to survive a long-term (>80 days), whereas all the nude mice
transferred with nondepleted spleen cells or the mixture of
CD25- cells and CD4+ T
cells (10% of which were CD25+ cells) in the
ratio 3:1 died of tumor progression within 40 days (Fig. 1B). Upon rechallenge with larger doses of RL1, the
CD25- cell-transferred nude mice rejected the
tumor inocula more rapidly and vigorously than the primary rejection,
indicating that they had become immune to the tumor (Fig. 1A, middle panel).
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1, in vitro stimulation of their
spleen cells with RL1 revealed two types of cytotoxic cells (type I
and II in Fig. 2, A and
B). The stimulated spleen cells from some mice specifically
killed RL1, but not allogeneic tumor cells such as B6-derived B16
melanoma cells (type I), while similarly stimulated spleen cells from
other mice killed not only RL1 but also B16 (type II). The former
type required in vitro stimulation with RL1 to become detectable,
whereas the latter did not. Furthermore, the former RL1-specific
killing was mediated by CD8+ CTLs: elimination of
CD8+ cells completely abolished the killing
activity, but that of CD4+ cells did not (Fig. 2C). On the other hand, the latter promiscuous killing
activity appeared to be mainly mediated by
CD4-8- cells because
elimination of both CD4+ cells and
CD8+ cells did not abrogate the activity (Fig. 2C). In these nude mice having developed
CD4-8- killer cells, the
retention of the killer activity after eliminating
CD8+ cells from the cultured spleen cells does
not necessarily mean that they did not harbor
CD8+ CTLs, because tumor-specific
CD8+ CTL clones could be easily prepared in vitro
from their spleens (29 , and our unpublished data).
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In vivo induction of tumor immunity by administration of anti-CD25 mAb
To determine whether transient elimination of
CD25+ cells from normal mice can also elicit
immunity to syngeneic tumors, we administered anti-CD25 mAb (PC61)
twice (on 4 and 2 days before tumor inoculation) to BALB/c or B6 mice,
and subsequently inoculated RL1 or B16 tumor cells, respectively
(Fig. 3). In the majority (>90%) of
PC61-treated BALB/c mice, the s.c. inoculated RL1 first grew and
then regressed within 1 mo, whereas all of the BALB/c mice treated with
normal rat Ig as a control died of tumor progression within 1 mo.
Likewise, administration of PC61 to B6 mice significantly suppressed
the growth of B16 when compared with control B6 mice treated with
normal rat IgG, allowing the former to survive a longer term (>60
days) compared with the latter (<40 days). This PC61 treatment reduced
the number of peripheral
CD25+4+ T cells to a
quarter of control mice for nearly 1 mo (our manuscript in
preparation). Furthermore, this in vitro anti-CD25 treatment evoked
rejection of various other syngeneic tumors in various other strains
(S. Onizuka, et al., manuscript in preparation).
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To examine whether similar cytotoxic lymphocytes as detected in
vivo (Figs. 1
and 2) can also be generated in vitro by simply
eliminating CD25+4+ T
cells, CD25- splenic cell suspensions prepared
from tumor-unsensitized normal BALB/c mice were cultured for several
days with or without RL1 cells and assessed for killing activity
(Fig. 4). Cells harvested on day 5 from
the RL1-stimulated culture indeed exhibited significant killing
activity against RL1 cells (Fig. 4A). Interestingly, when
CD25- spleen cells were cultured for 7 days,
potent cytotoxic activity was detected even in the cultures not
stimulated with RL1. By contrast, similarly cultured nondepleted
spleen cells or the mixtures of CD25- cells and
purified CD25+CD4+ T cells
(in the ratio 25:1 (see the inset in Fig. 4A))
showed no cytotoxicity. Furthermore, the cells harvested from the 7-day
culture killed not only RL1, which is NK sensitive
(27), but also NK-resistant tumor cells (such as P815) and
allogeneic ones (such as X5563 and B16) (Fig. 4B). This
promiscuous killing activity could not be toward calf serum proteins
adsorbed to the target cells during 51Cr
labeling, because tumor cells passaged in vivo and
51Cr labeled in the medium containing normal
mouse serum, instead of FCS, were lysed as well by
CD25- cell-derived cytotoxic cells (data not
shown). These findings were not confined to the BALB/c strain:
CD25- cells from other strains (including B6 and
C3H), when cultured for 1 wk without tumor cell stimulation, also gave
rise to cytotoxic cells promiscuously killing a broad spectrum of
syngeneic or allogeneic tumor cells (Fig. 4B).
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As shown in Fig. 4, there was no significant difference in the
killing activity or the killing spectrum of target tumor cells between
CD25- cells in vitro stimulated with tumor cells
for 7 days and those nonstimulated (see the inset in Fig. 4A). We therefore analyzed in the following experiments the
mechanism by which killer cells were generated from
CD25- cells cultured for 1 wk without in vitro
antigenic stimulation.
Fig. 5A shows that depletion
of either CD4+ cells or
CD8+ cells, or both, from the cell suspensions
harvested from 1-wk culture of CD25- BALB/c
spleen cells did not abrogate the cytotoxic activity against RL1 or
B16. The result indicates that the promiscuous killing activity was
mainly in the CD4-8-
population, although slight reduction of the killing activity by
depleting CD8+ cells suggests that
tumor-nonspecific CD8+ cytotoxic cells might also
be generated in the culture.
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/ß-TCR, or /-TCR Ab to the
51Cr release assay (Fig. 5B). None of
the Abs blocked the activity, in contrast to significant degrees of
blocking exerted by anti-CD8 or anti-/ß-TCR Ab on
allospecific CD8+ CTLs generated in vitro by
stimulating normal B6 spleen cells with BALB/c-derived RL1.
The lymphocytes harvested from 1-wk culture of B cell-depleted
CD25- spleen cells prepared from B6 mice were
composed of CD4+ T cells (
60%),
CD8+ T cells (30%), and
CD4-8- cells (10%)
(Fig. 5C). The
CD4-8- population
contained /ß-TCR+ cells (50%),
/-TCR+ cells (20%), and
NK1.1+ cells (30%) (Fig. 5C). The
population was mostly (>80%) B220+, and
contained CD122 (IL-2R ß-chain)+ cells
(70%), CD16+ cells (5%), and CD24 (heat
stable antigen (HSA))+ cells (5%) (data not
shown).
Furthermore, culturing CD25- splenic cells
prepared from B6-bg/bg mice, which are genetically defective
in NK cell-killing capacity (37), failed to generate the
promiscuous cytotoxic activity in the 1-wk culture, in contrast to
intact generation of allo-specific CTL activity by B6-bg/bg
mouse spleen cells stimulated with allogeneic RL1 cells (Fig. 6).
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The mechanism of spontaneous in vitro generation of CD4-8- cytotoxic cells
In the course of this in vitro generation of cytotoxic cells,
CD25- cells, especially
CD25-4+ T cells, showed
spontaneous and vigorous proliferation and secreted large amounts
(500 U/ml) of IL-2, whereas noneliminated spleen cells did not (Fig. 7, A and B). This
response was not against xenogeneic proteins in the culture medium,
because the use of normal BALB/c serum, instead of FCS, did not alter
the response (data not shown). On the other hand, the proliferative
response was blocked by adding anti-class II MHC Ab to the culture,
indicating that the proliferating CD4+ T cells
were presumably responding to self peptides/class II MHC complexes on
APCs (Fig. 7C).
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D, treatment d), whereas removal of
CD8+ T cells did not (Fig. 7D,
treatment c). On the other hand, addition of IL-2 (1000 U/ml) to the
culture of such CD4+ cell-depleted
CD25- cells (including
CD25-8+ cells and
CD4-8- cells) or
CD4-8- cells (Fig. 7D, treatment f and g, respectively) generated marked
cytotoxic activity, which was comparable with the activity generated by
culturing uneliminated spleen cells with the same dose of IL-2 (Fig. 7D, treatment h).
To further examine the key role of IL-2 secreted by
CD4+ T cells in generating
CD4-8- cytotoxic cells,
CD25-4+ T cells prepared
from IL-2-/-, IL-4-/-,
or IFN--/- mice on BALB/c background were
mixed with an equal number of
CD4-8- cells from normal
BALB/c mice and then assessed for cytotoxic activity after 1-wk culture
(Fig. 8).
CD25-4+ T cells from
IL-2-/- mice failed to generate the activity,
whereas those from IL-4-/- or
IFN--/- mice generated nearly equivalent
levels of killer activity as with
CD25-4+ T cells from
normal BALB/c mice.
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D, treatment h)) in their promiscuous cytotoxic activity
and the critical dependency of their generation upon IL-2
(38, 39, 40, 41, 42). T cell subpopulations required for autoimmunity
The CD25- cell-transferred nude mice that
had rejected tumor transplants (as shown in Fig. 1A)
developed histologically evident autoimmune diseases, including
gastritis (100% incidence, n = 14), thyroiditis
(42.9%), and oophoritis (64.3%) accompanying respective
autoantibodies (such as those specific for gastric parietal cells,
thyroglobulins, or oocytes (8, 13, 14)) (Fig. 9). Transfer of in vitro cultured
CD25- cells also produced similar autoimmune
diseases at similar incidences, whereas transfer of
CD4-8+ or
CD4-8- cells, or both,
prepared by eliminating CD4+ cells from the
cultured CD25- cells, did not. Thus,
CD4+ T cells were indispensable for producing
these organ-specific autoimmune diseases; and
CD8+ or
CD4-8- cells alone were
unable to cause the autoimmunity.
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did not develop histologically or serologically evident autoimmunity
(S.Y., J.S., S.S., unpublished data). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and in vitro
(Fig. 7A).
It has been postulated that one of the elements impeding effective
tumor immunity in tumor-bearing hosts may be concomitant development of
a T cell population suppressing the generation or the action of
tumor-killing effector cells (43, 44, 45). Although some of
such suppressor T cells were shown to be CD4+,
they have been elusive from further characterization because of the
lack of reliable markers specific for them (46). Our
results indicate that these suppressive T cells, at least in part, can
be CD25+4+ T cells. The
CD25+4+ immunoregulatory T
cells, however, bear several characteristics distinct from the
suppressor T cells to date reported in tumor immunity (43, 44). First, removal of
CD25+4+ T cells before
tumor implantation was effective in evoking specific tumor immunity in
vivo (Figs. 1 and 3) and in generating cytotoxic cells in vitro (Fig. 4). Second, their removal elicited not only tumor immunity, but also
various autoimmunities in vivo (Fig. 9) and self-reactivity in vitro
(Fig. 7). The removal also enhanced immune responses to allografts or
xenogeneic proteins (13). Third, they are continuously
produced by the normal thymus and already functional in the thymus, as
previously shown (14, 16, 17); and their depletion from
thymocyte suspensions indeed generated
CD4-8- NK-like killer
cells in vitro (our unpublished data) and autoimmunity in vivo
(17). Furthermore, these
CD25+4+ T cells/thymocytes
are naturally anergic (nonproliferative) to antigenic stimulation in
vitro, and, upon stimulation, potently suppress the
activation/proliferation of other CD4+ or
CD8+ T cells in an Ag-nonspecific manner through
cell to cell interactions on APCs (16, 17). These findings
when taken together indicate that the
CD25+4+ immunoregulatory T
cells present in normal naive mice may be engaged in continuously
up-regulating the activation thresholds of other T cells, thereby
impeding effective generation of tumor immunity while inhibiting
autoimmunity (16, 17, 18, 19). To further elucidate how they
suppress tumor immunity (and autoimmunity), the natural ligands
physiologically stimulating them must be characterized. Judging from
their activated phenotype (e.g., being CD25+,
CD45RBlow, CD44high, and
CD5high (8, 9, 11, 13, 16, 17)) in
normal naive mice, the
CD25+4+ immunoregulatory
T cells might be inherently reactive with, and continuously
stimulated by self Ags in the normal internal environment, although
they themselves may be harmless because of their anergic property
(16, 17).
Removal of CD25+4+
immunoregulatory cells led to the activation of not only tumor-specific
CD8+ CTLs (and presumably tumor-specific
CD4+ Th cells), but also tumor-nonspecific
CD4-8- effector cells in
vivo, and predominantly the latter in vitro. It also led to in vitro
vigorous proliferation of CD4+ self-reactive T
cells presumably responding to self peptides/class II MHC expressed on
APCs, as in the autologous or syngeneic mixed lymphocyte reaction
(47, 48). For the following reasons, it is the large
amounts of IL-2 formed by such CD4+ self-reactive
T cells that may be responsible for the generation of the
CD4-8- effector cells, at
least in vitro. First, similar cytotoxic cells could be generated by
adding an equivalent amount of IL-2 to the culture of normal spleen
cells or CD4-8- cells.
Second, CD25-4+ T cells
from IL-2-deficient mice failed to generate the cytotoxic cells from
the CD4-8- population in
normal mice. Third, the TCR-
CD4-8- cytotoxic cells
generated by culturing CD25- cells killed not
only NK-sensitive target cells (such as RL1 (27)), but
also NK-resistant ones (such as P815), as IL-2-induced LAK cells can
kill a broader spectrum of tumors than NK cells (49). The
majority of such CD25- cell-derived killer cells
indeed appeared to be NK cells in terms of their cell surface phenotype
(e.g., NK1.1+, B220+),
marked IL-2 dependency in their generation, and the lack of
tumor-killing activity in beige mice (38, 39, 40, 41, 42). Taken
together, these results indicate that active NK cells as LAK cells can
be easily generated in vitro by simply eliminating a T cell
subpopulation, without exogenous IL-2.
It remains to be determined, however, how in vivo removal of
CD25+4+ T cells leads to
the generation of two distinct types of effector cells (tumor-specific
CD8+ CTLs and tumor-nonspecific
CD4-8- NK-like cells
(Fig. 2)), or whether CD4+ self-reactive T cells
play key roles in the in vivo generation of tumor immunity as well by
secreting large amounts of IL-2. By in vivo administration of
anti-CD25 Ab (Fig. 3),
CD4-8- LAK/NK-like cells
indeed appeared within 1 wk, followed by dominant development of
tumor-specific CD8+ CTLs, which seemed to play
main roles in ultimate tumor rejection (our manuscript in preparation).
The result suggests that in vivo removal of
CD25+4+ cells may first
activate LAK/NK cells by activating CD4+
self-reactive T cells and instigating their IL-2 secretion; and
tumor-nonspecific killing by such LAK/NK cells and consequent release
of tumor Ags, together with the IL-2 secreted by
CD4+ self-reactive T cells, may contribute to the
subsequent development of tumor-specific CD8+
CTLs. Alternatively, although mutually not exclusive, the removal of
CD25+4+ cells may enhance
the development of both LAK/NK cells (through activating
CD4+ self-reactive T cells) and
CD8+ CTLs (and tumor-specific
CD4+ Th cells) at the same time, because the
immunoregulatory CD25+4+ T
cells can directly suppress the activation/proliferation of both
CD4+ T cells and CD8+ T
cells, at least in vitro (16, 17). Further analysis of the
in vivo interplay of the two types of effector cells in tumor immunity
may contribute to our devising effective ways to generate them in
vitro, especially tumor-specific CD8+
CTLs.
A critical issue in our study is how tumor immunity can be evoked
without autoimmunity when the
CD25+4+ immunoregulatory T
cells are manipulated. The present and previous studies by us and
others have shown that, upon introduction of abnormal control of
self-reactive T cells, the intensity and the range of the autoimmune
responses (i.e., which self Ags are more prone to be aggressed, or
which self-reactive clones are more prone to be activated) depend on
the effector T cell subpopulations involved, the degree and duration of
depleting CD25+4+ T cells,
and, most importantly, the host genetic background, which includes MHC
as well as non-MHC genes (7, 13, 18, 50, 51, 52, 53). For example,
when CD4+ T cells are depleted from in vitro
cultured CD25- cells and the remaining cells,
including CD8+ or
CD4-8- cytotoxic cells,
are adoptively transferred, no histologically and serologically evident
autoimmune disease developed in the recipients (Fig. 9), presumably
because CD4+ effector T cells are required for
the development of this organ-specific autoimmunity as in many other
models (8, 9, 10, 11, 12, 13, 14, 50, 51, 52, 53, 54). Furthermore, in BALB/c mice, which
are genetically prone to develop organ-specific autoimmune diseases (in
particular autoimmune gastritis (13, 14, 18, 50, 51, 52, 53)),
limiting the period or the degree of depleting
CD25+ T cells, for example, by in vivo
administration of anti-CD25 Ab for a short period, could evoke
effective tumor immunity without autoimmunity (Fig. 3, and our
manuscript in preparation). In genetically autoimmune-resistant B6 mice
(18, 50, 51, 52, 53), on the other hand, complete depletion of
CD25+4+ T cells from the
cell inocula (as shown in Fig. 1A) led to tumor rejection,
but failed to cause any autoimmune disease in B6 nude mice (our
unpublished result). To further differentiate tumor immunity from
autoimmunity, it is required to elucidate the molecular basis of the
CD25+ T cell-mediated immunoregulation and the
host genes determining the susceptibility/resistance to
autoimmunity.
Thus, with a caveat of possible autoimmunity in certain situations (see discussion above), the present findings in mice may help to devise a novel immunotherapy for cancer in humans or to make the current immunotherapies more effective. For example, administration of anti-CD25 Ab to cancer-bearing hosts for a limited period may evoke or enhance tumor immunity. Removal of CD25+4+ T cells from PBL or tumor-infiltrating T cells before their in vitro culture with IL-2 may lead to production of more potent or a larger number of cytotoxic cells, including CTLs and LAK/NK cells (40, 45, 55). Furthermore, such in vivo or in vitro elimination of the CD25+4+ immunoregulatory T cells may enhance tumor immunity when combined with the current attempts to augment immunogenicity of tumor cells, for example, by cytokine gene transduction in tumor cells, or vaccination with tumor Ags/peptides or Ag-pulsed dendritic cells (56, 57).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shimon Sakaguchi, Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Shogoin Kawahara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. E-mail address:
3 Abbreviations used in this paper: bg, beige; C, complement; LAK, lymphokine-activated killer.
Received for publication April 26, 1999. Accepted for publication August 25, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
-chain (CD25) and having a functionally transient nature into memory cells. Int. Immunol. 3:1349. genes. Science 259:1739.1 by cell-mediated cytotoxicity. Proc. Natl. Acad. Sci. USA 76:3486.1 leukemia recognized by cytotoxic T lymphocytes and its relation to the akt oncogene. J. Exp. Med. 180:1599.-ßTCR+ CD4- CD8- and -TCR+ CD4- CD8- cells. J. Exp. Med. 179:1957.This article has been cited by other articles:
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  S. Kimpfler, A. Sevko, S. Ring, C. Falk, W. Osen, K. Frank, M. Kato, K. Mahnke, D. Schadendorf, and V. Umansky Skin Melanoma Development in ret Transgenic Mice Despite the Depletion of CD25+Foxp3+ Regulatory T Cells in Lymphoid Organs J. Immunol., November 15, 2009; 183(10): 6330 - 6337. [Abstract] [Full Text] [PDF]
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 M. G. LaCelle, S. M. Jensen, and B. A. Fox Partial CD4 Depletion Reduces Regulatory T Cells Induced by Multiple Vaccinations and Restores Therapeutic Efficacy Clin. Cancer Res., November 15, 2009; 15(22): 6881 - 6890. [Abstract] [Full Text] [PDF]
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 L. R. Guerin, J. R. Prins, and S. A. Robertson Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum. Reprod. Update, September 1, 2009; 15(5): 517 - 535. [Abstract] [Full Text] [PDF]
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A. Andersson, S.-C. Yang, M. Huang, L. Zhu, U. K. Kar, R. K. Batra, D. Elashoff, R. M. Strieter, S. M. Dubinett, and S. Sharma IL-7 Promotes CXCR3 Ligand-Dependent T Cell Antitumor Reactivity in Lung Cancer J. Immunol., June 1, 2009; 182(11): 6951 - 6958. [Abstract] [Full Text] [PDF]
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 I. Horkheimer, M. Quigley, J. Zhu, X. Huang, N. J. Chao, and Y. Yang Induction of type I IFN is required for overcoming tumor-specific T-cell tolerance after stem cell transplantation Blood, May 21, 2009; 113(21): 5330 - 5339. [Abstract] [Full Text] [PDF]
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Y.-C. Lin, L.-Y. Chang, C.-T. Huang, H.-M. Peng, A. Dutta, T.-C. Chen, C.-T. Yeh, and C.-Y. Lin Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity J. Immunol., May 15, 2009; 182(10): 6095 - 6104. [Abstract] [Full Text] [PDF]
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 V. Francois, S. Ottaviani, N. Renkvist, J. Stockis, G. Schuler, K. Thielemans, D. Colau, M. Marchand, T. Boon, S. Lucas, et al. The CD4+ T-Cell Response of Melanoma Patients to a MAGE-A3 Peptide Vaccine Involves Potential Regulatory T Cells Cancer Res., May 15, 2009; 69(10): 4335 - 4345. [Abstract] [Full Text] [PDF]
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M. J. Szczepanski, M. Szajnik, M. Czystowska, M. Mandapathil, L. Strauss, A. Welsh, K. A. Foon, T. L. Whiteside, and M. Boyiadzis Increased Frequency and Suppression by Regulatory T Cells in Patients with Acute Myelogenous Leukemia Clin. Cancer Res., May 15, 2009; 15(10): 3325 - 3332. [Abstract] [Full Text] [PDF]
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 K. TOKUNO, S. HAZAMA, S. YOSHINO, S. YOSHIDA, and M. OKA Increased Prevalence of Regulatory T-Cells in the Peripheral Blood of Patients with Gastrointestinal Cancer Anticancer Res, May 1, 2009; 29(5): 1527 - 1532. [Abstract] [Full Text] [PDF]
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C.-H. Lee, Y.-H. Chiang, S.-E. Chang, C.-L. Chong, B.-M. Cheng, and S. R. Roffler Tumor-Localized Ligation of CD3 and CD28 with Systemic Regulatory T-Cell Depletion Induces Potent Innate and Adaptive Antitumor Responses Clin. Cancer Res., April 15, 2009; 15(8): 2756 - 2766. [Abstract] [Full Text] [PDF]
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J. H. Maxeiner, R. Karwot, K. Sauer, P. Scholtes, I. Boross, M. Koslowski, O. Tureci, R. Wiewrodt, M. F. Neurath, H. A. Lehr, et al. A Key Regulatory Role of the Transcription Factor NFATc2 in Bronchial Adenocarcinoma via CD8+ T Lymphocytes Cancer Res., April 1, 2009; 69(7): 3069 - 3076. [Abstract] [Full Text] [PDF]
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J. WADA, H. SUZUKI, R. FUCHINO, A. YAMASAKI, S. NAGAI, K. YANAI, K. KOGA, M. NAKAMURA, M. TANAKA, T. MORISAKI, et al. The Contribution of Vascular Endothelial Growth Factor to the Induction of Regulatory T-Cells in Malignant Effusions Anticancer Res, March 1, 2009; 29(3): 881 - 888. [Abstract] [Full Text] [PDF]
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M. C. B. Tan, P. S. Goedegebuure, B. A. Belt, B. Flaherty, N. Sankpal, W. E. Gillanders, T. J. Eberlein, C.-S. Hsieh, and D. C. Linehan Disruption of CCR5-Dependent Homing of Regulatory T Cells Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer J. Immunol., February 1, 2009; 182(3): 1746 - 1755. [Abstract] [Full Text] [PDF]
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K. A. Pilones, N. Kawashima, A. M. Yang, J. S. Babb, S. C. Formenti, and S. Demaria Invariant Natural Killer T Cells Regulate Breast Cancer Response to Radiation and CTLA-4 Blockade Clin. Cancer Res., January 15, 2009; 15(2): 597 - 606. [Abstract] [Full Text] [PDF]
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Y. Han, Q. Guo, M. Zhang, Z. Chen, and X. Cao CD69+CD4+CD25- T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-{beta}1 J. Immunol., January 1, 2009; 182(1): 111 - 120. [Abstract] [Full Text] [PDF]
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J. HIGASHIJIMA, M. SHIMADA, M. CHIKAKIYO, T. MIYATANI, K. YOSHIKAWA, M. NISHIOKA, T. IWATA, and N. KURITA Effect of Splenectomy on Antitumor Immune System in Mice Anticancer Res, January 1, 2009; 29(1): 385 - 393. [Abstract] [Full Text] [PDF]
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 K. Wing, Y. Onishi, P. Prieto-Martin, T. Yamaguchi, M. Miyara, Z. Fehervari, T. Nomura, and S. Sakaguchi CTLA-4 Control over Foxp3+ Regulatory T Cell Function Science, October 10, 2008; 322(5899): 271 - 275. [Abstract] [Full Text] [PDF]
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 J. King, J. Waxman, and H. Stauss Advances in tumour immunotherapy QJM, September 1, 2008; 101(9): 675 - 683. [Abstract] [Full Text] [PDF]
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S. Watanabe, K. Deguchi, R. Zheng, H. Tamai, L.-x. Wang, P. A. Cohen, and S. Shu Tumor-Induced CD11b+Gr-1+ Myeloid Cells Suppress T Cell Sensitization in Tumor-Draining Lymph Nodes J. Immunol., September 1, 2008; 181(5): 3291 - 3300. [Abstract] [Full Text] [PDF]
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A. Laronne-Bar-On, D. Zipori, and N. Haran-Ghera Increased Regulatory versus Effector T Cell Development Is Associated with Thymus Atrophy in Mouse Models of Multiple Myeloma J. Immunol., September 1, 2008; 181(5): 3714 - 3724. [Abstract] [Full Text] [PDF]
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H. Nishikawa, T. Kato, M. Hirayama, Y. Orito, E. Sato, N. Harada, S. Gnjatic, L. J. Old, and H. Shiku Regulatory T Cell-Resistant CD8+ T Cells Induced by Glucocorticoid-Induced Tumor Necrosis Factor Receptor Signaling Cancer Res., July 15, 2008; 68(14): 5948 - 5954. [Abstract] [Full Text] [PDF]
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M. J. Gough, C. E. Ruby, W. L. Redmond, B. Dhungel, A. Brown, and A. D. Weinberg OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor Cancer Res., July 1, 2008; 68(13): 5206 - 5215. [Abstract] [Full Text] [PDF]
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L. Gil-Guerrero, J. Dotor, I. L. Huibregtse, N. Casares, A. B. Lopez-Vazquez, F. Rudilla, J. I. Riezu-Boj, J. Lopez-Sagaseta, J. Hermida, S. Van Deventer, et al. In Vitro and In Vivo Down-Regulation of Regulatory T Cell Activity with a Peptide Inhibitor of TGF-{beta}1 J. Immunol., July 1, 2008; 181(1): 126 - 135. [Abstract] [Full Text] [PDF]
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J. Kline, I. E. Brown, Y.-Y. Zha, C. Blank, J. Strickler, H. Wouters, L. Zhang, and T. F. Gajewski Homeostatic Proliferation Plus Regulatory T-Cell Depletion Promotes Potent Rejection of B16 Melanoma Clin. Cancer Res., May 15, 2008; 14(10): 3156 - 3167. [Abstract] [Full Text] [PDF]
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M. E. C. Lutsiak, Y. Tagaya, A. J. Adams, J. Schlom, and H. Sabzevari Tumor-Induced Impairment of TCR Signaling Results in Compromised Functionality of Tumor-Infiltrating Regulatory T Cells J. Immunol., May 1, 2008; 180(9): 5871 - 5881. [Abstract] [Full Text] [PDF]
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 S. Piconese, B. Valzasina, and M. P. Colombo OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection J. Exp. Med., April 14, 2008; 205(4): 825 - 839. [Abstract] [Full Text] [PDF]
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 N. Larmonier, J. Cantrell, C. LaCasse, G. Li, N. Janikashvili, E. Situ, M. Sepassi, S. Andreansky, and E. Katsanis Chaperone-rich tumor cell lysate-mediated activation of antigen-presenting cells resists regulatory T cell suppression J. Leukoc. Biol., April 1, 2008; 83(4): 1049 - 1059. [Abstract] [Full Text] [PDF]
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X. Feng, S. Kajigaya, E. E. Solomou, K. Keyvanfar, X. Xu, N. Raghavachari, P. J. Munson, T. M. Herndon, J. Chen, and N. S. Young Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro Blood, April 1, 2008; 111(7): 3675 - 3683. [Abstract] [Full Text] [PDF]
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 L. Mascitelli and F. Pezzetta Regulatory T Cells, Allergic Diseases, and Cancer Chest, March 1, 2008; 133(3): 832 - 832. [Full Text] [PDF]
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J. Yokokawa, V. Cereda, C. Remondo, J. L. Gulley, P. M. Arlen, J. Schlom, and K. Y. Tsang Enhanced Functionality of CD4+CD25highFoxP3+ Regulatory T Cells in the Peripheral Blood of Patients with Prostate Cancer Clin. Cancer Res., February 15, 2008; 14(4): 1032 - 1040. [Abstract] [Full Text] [PDF]
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H. Nishikawa, T. Tsuji, E. Jager, G. Briones, G. Ritter, L. J. Old, J. E. Galan, H. Shiku, and S. Gnjatic Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector Blood, February 1, 2008; 111(3): 1404 - 1412. [Abstract] [Full Text] [PDF]
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P. Hu, R. S. Arias, R. E. Sadun, Y.-C. Nien, N. Zhang, H. Sabzevari, M.E. C. Lutsiak, L. A. Khawli, and A. L. Epstein Construction and Preclinical Characterization of Fc-mGITRL for the Immunotherapy of Cancer Clin. Cancer Res., January 15, 2008; 14(2): 579 - 588. [Abstract] [Full Text] [PDF]
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J. Haas, L. Schopp, B. Storch-Hagenlocher, B. Fritzsching, C. Jacobi, L. Milkova, B. Fritz, A. Schwarz, E. Suri-Payer, M. Hensel, et al. Specific recruitment of regulatory T cells into the CSF in lymphomatous and carcinomatous meningitis Blood, January 15, 2008; 111(2): 761 - 766. [Abstract] [Full Text] [PDF]
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E. Degl'Innocenti, M. Grioni, G. Capuano, E. Jachetti, M. Freschi, M. T.S. Bertilaccio, R. Hess-Michelini, C. Doglioni, and M. Bellone Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells Cancer Res., January 1, 2008; 68(1): 292 - 300. [Abstract] [Full Text] [PDF]
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Y. Li and C. Yee IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes Blood, January 1, 2008; 111(1): 229 - 235. [Abstract] [Full Text] [PDF]
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 L. Vence, A. K. Palucka, J. W. Fay, T. Ito, Y.-J. Liu, J. Banchereau, and H. Ueno Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma PNAS, December 26, 2007; 104(52): 20884 - 20889. [Abstract] [Full Text] [PDF]
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P. Zhou, L. L'italien, D. Hodges, and X. M. Schebye Pivotal Roles of CD4+ Effector T cells in Mediating Agonistic Anti-GITR mAb-Induced-Immune Activation and Tumor Immunity in CT26 Tumors J. Immunol., December 1, 2007; 179(11): 7365 - 7375. [Abstract] [Full Text] [PDF]
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 T. L. Guo, R. P. Chi, D. M. Hernandez, W. Auttachoat, and J. F. Zheng Decreased 7,12-dimethylbenz[a]anthracene-induced carcinogenesis coincides with the induction of antitumor immunities in adult female B6C3F1 mice pretreated with genistein Carcinogenesis, December 1, 2007; 28(12): 2560 - 2566. [Abstract] [Full Text] [PDF]
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K. Leon, K. Garcia, J. Carneiro, and A. Lage How Regulatory CD25+CD4+ T Cells Impinge on Tumor Immunobiology: The Differential Response of Tumors to Therapies J. Immunol., November 1, 2007; 179(9): 5659 - 5668. [Abstract] [Full Text] [PDF]
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M. T. Litzinger, R. Fernando, T. J. Curiel, D. W. Grosenbach, J. Schlom, and C. Palena IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity Blood, November 1, 2007; 110(9): 3192 - 3201. [Abstract] [Full Text] [PDF]
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 R. Sutmuller, A. Garritsen, and G. J Adema Regulatory T cells and toll-like receptors: regulating the regulators Ann Rheum Dis, November 1, 2007; 66(suppl_3): iii91 - iii95. [Abstract] [Full Text] [PDF]
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N. Chaput, G. Darrasse-Jeze, A.-S. Bergot, C. Cordier, S. Ngo-Abdalla, D. Klatzmann, and O. Azogui Regulatory T Cells Prevent CD8 T Cell Maturation by Inhibiting CD4 Th Cells at Tumor Sites J. Immunol., October 15, 2007; 179(8): 4969 - 4978. [Abstract] [Full Text] [PDF]
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E. Ambrosino, M. Terabe, R. C. Halder, J. Peng, S. Takaku, S. Miyake, T. Yamamura, V. Kumar, and J. A. Berzofsky Cross-Regulation between Type I and Type II NKT Cells in Regulating Tumor Immunity: A New Immunoregulatory Axis J. Immunol., October 15, 2007; 179(8): 5126 - 5136. [Abstract] [Full Text] [PDF]
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C. E. Clark, S. R. Hingorani, R. Mick, C. Combs, D. A. Tuveson, and R. H. Vonderheide Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion Cancer Res., October 1, 2007; 67(19): 9518 - 9527. [Abstract] [Full Text] [PDF]
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S. Brouard, E. Mansfield, C. Braud, L. Li, M. Giral, S.-c. Hsieh, D. Baeten, M. Zhang, J. Ashton-Chess, C. Braudeau, et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance PNAS, September 25, 2007; 104(39): 15448 - 15453. [Abstract] [Full Text] [PDF]
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N. Hyka-Nouspikel, L. Lucian, E. Murphy, T. McClanahan, and J. H. Phillips DAP10 Deficiency Breaks the Immune Tolerance against Transplantable Syngeneic Melanoma J. Immunol., September 15, 2007; 179(6): 3763 - 3771. [Abstract] [Full Text] [PDF]
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C. M. Paulos, A. Kaiser, C. Wrzesinski, C. S. Hinrichs, L. Cassard, A. Boni, P. Muranski, L. Sanchez-Perez, D. C. Palmer, Z. Yu, et al. Toll-like Receptors in Tumor Immunotherapy Clin. Cancer Res., September 15, 2007; 13(18): 5280 - 5289. [Abstract] [Full Text] [PDF]
|
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V. S. Zimmermann, A. Casati, C. Schiering, S. Caserta, R. Hess Michelini, V. Basso, and A. Mondino Tumors Hamper the Immunogenic Competence of CD4+ T Cell-Directed Dendritic Cell Vaccination J. Immunol., September 1, 2007; 179(5): 2899 - 2909. [Abstract] [Full Text] [PDF]
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R. Harrop, N. Drury, W. Shingler, P. Chikoti, I. Redchenko, M. W. Carroll, S. M. Kingsman, S. Naylor, A. Melcher, J. Nicholls, et al. Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Encoding the Tumor Antigen 5T4 (TroVax) Given Alongside Chemotherapy Induces Potent Immune Responses Clin. Cancer Res., August 1, 2007; 13(15): 4487 - 4494. [Abstract] [Full Text] [PDF]
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 P. Sabbatini and K. Odunsi Immunologic Approaches to Ovarian Cancer Treatment J. Clin. Oncol., July 10, 2007; 25(20): 2884 - 2893. [Abstract] [Full Text] [PDF]
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P. Zhang, A. L. Cote, V. C. de Vries, E. J. Usherwood, and M. J. Turk Induction of Postsurgical Tumor Immunity and T-Cell Memory by a Poorly Immunogenic Tumor Cancer Res., July 1, 2007; 67(13): 6468 - 6476. [Abstract] [Full Text] [PDF]
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S. Tuve, B.-M. Chen, Y. Liu, T.-L. Cheng, P. Toure, P. S. Sow, Q. Feng, N. Kiviat, R. Strauss, S. Ni, et al. Combination of Tumor Site-Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses Cancer Res., June 15, 2007; 67(12): 5929 - 5939. [Abstract] [Full Text] [PDF]
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R. P. Singh, A. La Cava, M. Wong, F. Ebling, and B. H. Hahn CD8+ T Cell-Mediated Suppression of Autoimmunity in a Murine Lupus Model of Peptide-Induced Immune Tolerance Depends on Foxp3 Expression J. Immunol., June 15, 2007; 178(12): 7649 - 7657. [Abstract] [Full Text] [PDF]
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K. G. Elpek, C. Lacelle, N. P. Singh, E. S. Yolcu, and H. Shirwan CD4+CD25+ T Regulatory Cells Dominate Multiple Immune Evasion Mechanisms in Early but Not Late Phases of Tumor Development in a B Cell Lymphoma Model J. Immunol., June 1, 2007; 178(11): 6840 - 6848. [Abstract] [Full Text] [PDF]
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Y. H. Kim, M. Duvic, E. Obitz, R. Gniadecki, L. Iversen, A. Osterborg, S. Whittaker, T. M. Illidge, T. Schwarz, R. Kaufmann, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma Blood, June 1, 2007; 109(11): 4655 - 4662. [Abstract] [Full Text] [PDF]
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L. Weng, J. Dyson, and F. Dazzi Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment PNAS, May 15, 2007; 104(20): 8415 - 8420. [Abstract] [Full Text] [PDF]
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P. Sinha, V. K. Clements, A. M. Fulton, and S. Ostrand-Rosenberg Prostaglandin E2 Promotes Tumor Progression by Inducing Myeloid-Derived Suppressor Cells Cancer Res., May 1, 2007; 67(9): 4507 - 4513. [Abstract] [Full Text] [PDF]
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G. Rudge, S. P. Barrett, B. Scott, and I. R. van Driel Infiltration of a Mesothelioma by IFN-{gamma}-Producing Cells and Tumor Rejection after Depletion of Regulatory T Cells J. Immunol., April 1, 2007; 178(7): 4089 - 4096. [Abstract] [Full Text] [PDF]
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K. N. Couper, D. G. Blount, J. B. de Souza, I. Suffia, Y. Belkaid, and E. M. Riley Incomplete Depletion and Rapid Regeneration of Foxp3+ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice J. Immunol., April 1, 2007; 178(7): 4136 - 4146. [Abstract] [Full Text] [PDF]
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U. Galili, K. Wigglesworth, and U. M. Abdel-Motal Intratumoral Injection of {alpha}-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines J. Immunol., April 1, 2007; 178(7): 4676 - 4687. [Abstract] [Full Text] [PDF]
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C. Kudo-Saito, E. K. Wansley, M. E. Gruys, R. Wiltrout, J. Schlom, and J. W. Hodge Combination Therapy of an Orthotopic Renal Cell Carcinoma Model Using Intratumoral Vector-Mediated Costimulation and Systemic Interleukin-2 Clin. Cancer Res., March 15, 2007; 13(6): 1936 - 1946. [Abstract] [Full Text] [PDF]
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M. S. Turner, P. A. Cohen, and O. J. Finn Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells J. Immunol., March 1, 2007; 178(5): 2787 - 2793. [Abstract] [Full Text] [PDF]
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V. C. Liu, L. Y. Wong, T. Jang, A. H. Shah, I. Park, X. Yang, Q. Zhang, S. Lonning, B. A. Teicher, and C. Lee Tumor Evasion of the Immune System by Converting CD4+CD25- T Cells into CD4+CD25+ T Regulatory Cells: Role of Tumor-Derived TGF-beta J. Immunol., March 1, 2007; 178(5): 2883 - 2892. [Abstract] [Full Text] [PDF]
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S. Liu, D. R. Breiter, G. Zheng, and A. Chen Enhanced Antitumor Responses Elicited by Combinatorial Protein Transfer of Chemotactic and Costimulatory Molecules J. Immunol., March 1, 2007; 178(5): 3301 - 3306. [Abstract] [Full Text] [PDF]
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G. Zhou and H. I. Levitsky Natural Regulatory T Cells and De Novo-Induced Regulatory T Cells Contribute Independently to Tumor-Specific Tolerance J. Immunol., February 15, 2007; 178(4): 2155 - 2162. [Abstract] [Full Text] [PDF]
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A. Chen, S. Liu, D. Park, Y. Kang, and G. Zheng Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer Cancer Res., February 1, 2007; 67(3): 1291 - 1298. [Abstract] [Full Text] [PDF]
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N. Kobayashi, N. Hiraoka, W. Yamagami, H. Ojima, Y. Kanai, T. Kosuge, A. Nakajima, and S. Hirohashi FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis Clin. Cancer Res., February 1, 2007; 13(3): 902 - 911. [Abstract] [Full Text] [PDF]
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S. Nair, D. Boczkowski, M. Fassnacht, D. Pisetsky, and E. Gilboa Vaccination against the Forkhead Family Transcription Factor Foxp3 Enhances Tumor Immunity Cancer Res., January 1, 2007; 67(1): 371 - 380. [Abstract] [Full Text] [PDF]
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N. Ralainirina, A. Poli, T. Michel, L. Poos, E. Andres, F. Hentges, and J. Zimmer Control of NK cell functions by CD4+CD25+ regulatory T cells J. Leukoc. Biol., January 1, 2007; 81(1): 144 - 153. [Abstract] [Full Text] [PDF]
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A. Charalambous, M. Oks, G. Nchinda, S. Yamazaki, and R. M. Steinman Dendritic Cell Targeting of Survivin Protein in a Xenogeneic Form Elicits Strong CD4+ T Cell Immunity to Mouse Survivin J. Immunol., December 15, 2006; 177(12): 8410 - 8421. [Abstract] [Full Text] [PDF]
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M. J. Dobrzanski, J. B. Reome, J. C. Hylind, and K. A. Rewers-Felkins CD8-Mediated Type 1 Antitumor Responses Selectively Modulate Endogenous Differentiated and Nondifferentiated T Cell Localization, Activation, and Function in Progressive Breast Cancer J. Immunol., December 1, 2006; 177(11): 8191 - 8201. [Abstract] [Full Text] [PDF]
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Z.-Z. Yang, A. J. Novak, S. C. Ziesmer, T. E. Witzig, and S. M. Ansell Attenuation of CD8+ T-Cell Function by CD4+CD25+ Regulatory T Cells in B-Cell Non-Hodgkin's Lymphoma. Cancer Res., October 15, 2006; 66(20): 10145 - 10152. [Abstract] [Full Text] [PDF]
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S. Read, R. Greenwald, A. Izcue, N. Robinson, D. Mandelbrot, L. Francisco, A. H. Sharpe, and F. Powrie Blockade of CTLA-4 on CD4+CD25+ Regulatory T Cells Abrogates Their Function In Vivo J. Immunol., October 1, 2006; 177(7): 4376 - 4383. [Abstract] [Full Text] [PDF]
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 L. Melencio, R. J. McKallip, H. Guan, R. Ramakrishnan, R. Jain, P. S. Nagarkatti, and M. Nagarkatti Role of CD4+CD25+ T regulatory cells in IL-2-induced vascular leak Int. Immunol., October 1, 2006; 18(10): 1461 - 1471. [Abstract] [Full Text] [PDF]
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N. Hiraoka, K. Onozato, T. Kosuge, and S. Hirohashi Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions. Clin. Cancer Res., September 15, 2006; 12(18): 5423 - 5434. [Abstract] [Full Text] [PDF]
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 A. Vojdani and J. Erde Regulatory T Cells, a Potent Immunoregulatory Target for CAM Researchers: Modulating Tumor Immunity, Autoimmunity and Alloreactive Immunity (III) Evid. Based Complement. Altern. Med., September 1, 2006; 3(3): 309 - 316. [Abstract] [Full Text] [PDF]
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G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms. Clin. Cancer Res., August 15, 2006; 12(16): 4794 - 4803. [Abstract] [Full Text] [PDF]
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M. Maksimow, M. Miiluniemi, F. Marttila-Ichihara, S. Jalkanen, and A. Hanninen Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity Blood, August 15, 2006; 108(4): 1298 - 1305. [Abstract] [Full Text] [PDF]
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E. Ambrosino, M. Spadaro, M. Iezzi, C. Curcio, G. Forni, P. Musiani, W.-Z. Wei, and F. Cavallo Immunosurveillance of erbb2 carcinogenesis in transgenic mice is concealed by a dominant regulatory T-cell self-tolerance. Cancer Res., August 1, 2006; 66(15): 7734 - 7740. [Abstract] [Full Text] [PDF]
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N. Sugimoto, T. Oida, K. Hirota, K. Nakamura, T. Nomura, T. Uchiyama, and S. Sakaguchi Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis Int. Immunol., August 1, 2006; 18(8): 1197 - 1209. [Abstract] [Full Text] [PDF]
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M. Beyer and J. L. Schultze Regulatory T cells in cancer Blood, August 1, 2006; 108(3): 804 - 811. [Abstract] [Full Text] [PDF]
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J. D. Bui, R. Uppaluri, C.-S. Hsieh, and R. D. Schreiber Comparative Analysis of Regulatory and Effector T Cells in Progressively Growing versus Rejecting Tumors of Similar Origins. Cancer Res., July 15, 2006; 66(14): 7301 - 7309. [Abstract] [Full Text] [PDF]
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P. E. Fecci, A. E. Sweeney, P. M. Grossi, S. K. Nair, C. A. Learn, D. A. Mitchell, X. Cui, T. J. Cummings, D. D. Bigner, E. Gilboa, et al. Systemic Anti-CD25 Monoclonal Antibody Administration Safely Enhances Immunity in Murine Glioma without Eliminating Regulatory T Cells. Clin. Cancer Res., July 15, 2006; 12(14): 4294 - 4305. [Abstract] [Full Text] [PDF]
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R. Zeiser, V. H. Nguyen, A. Beilhack, M. Buess, S. Schulz, J. Baker, C. H. Contag, and R. S. Negrin Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production Blood, July 1, 2006; 108(1): 390 - 399. [Abstract] [Full Text] [PDF]
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S. Oniki, H. Nagai, T. Horikawa, J. Furukawa, M. L. Belladonna, T. Yoshimoto, I. Hara, and C. Nishigori Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res., June 15, 2006; 66(12): 6395 - 6404. [Abstract] [Full Text] [PDF]
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T. Ishida, T. Ishii, A. Inagaki, H. Yano, H. Komatsu, S. Iida, H. Inagaki, and R. Ueda Specific Recruitment of CC Chemokine Receptor 4-Positive Regulatory T Cells in Hodgkin Lymphoma Fosters Immune Privilege Cancer Res., June 1, 2006; 66(11): 5716 - 5722. [Abstract] [Full Text] [PDF]
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T. Ramirez-Montagut, A. Chow, D. Hirschhorn-Cymerman, T. H. Terwey, A. A. Kochman, S. Lu, R. C. Miles, S. Sakaguchi, A. N. Houghton, and M. R. M. van den Brink Glucocorticoid-Induced TNF Receptor Family Related Gene Activation Overcomes Tolerance/Ignorance to Melanoma Differentiation Antigens and Enhances Antitumor Immunity. J. Immunol., June 1, 2006; 176(11): 6434 - 6442. [Abstract] [Full Text] [PDF]
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H. Offner, S. Subramanian, S. M. Parker, C. Wang, M. E. Afentoulis, A. Lewis, A. A. Vandenbark, and P. D. Hurn Splenic Atrophy in Experimental Stroke Is Accompanied by Increased Regulatory T Cells and Circulating Macrophages. J. Immunol., June 1, 2006; 176(11): 6523 - 6531. [Abstract] [Full Text] [PDF]
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T. Nishioka, J. Shimizu, R. Iida, S. Yamazaki, and S. Sakaguchi CD4+CD25+Foxp3+ T Cells and CD4+CD25-Foxp3+ T Cells in Aged Mice. J. Immunol., June 1, 2006; 176(11): 6586 - 6593. [Abstract] [Full Text] [PDF]
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M. Veldhoen, H. Moncrieffe, R. J. Hocking, C. J. Atkins, and B. Stockinger Modulation of Dendritic Cell Function by Naive and Regulatory CD4+ T Cells J. Immunol., May 15, 2006; 176(10): 6202 - 6210. [Abstract] [Full Text] [PDF]
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H. Nishikawa, F. Qian, T. Tsuji, G. Ritter, L. J. Old, S. Gnjatic, and K. Odunsi Influence of CD4+CD25+ Regulatory T Cells on Low/High-Avidity CD4+ T Cells following Peptide Vaccination J. Immunol., May 15, 2006; 176(10): 6340 - 6346. [Abstract] [Full Text] [PDF]
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M. Beyer, M. Kochanek, T. Giese, E. Endl, M. R. Weihrauch, P. A. Knolle, S. Classen, and J. L. Schultze In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma Blood, May 15, 2006; 107(10): 3940 - 3949. [Abstract] [Full Text] [PDF]
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D.-M. Zhao, A. M. Thornton, R. J. DiPaolo, and E. M. Shevach Activated CD4+CD25+ T cells selectively kill B lymphocytes Blood, May 15, 2006; 107(10): 3925 - 3932. [Abstract] [Full Text] [PDF]
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A. D. Cohen, A. Diab, M.-A. Perales, J. D. Wolchok, G. Rizzuto, T. Merghoub, D. Huggins, C. Liu, M. J. Turk, N. P. Restifo, et al. Agonist Anti-GITR Antibody Enhances Vaccine-Induced CD8+ T-Cell Responses and Tumor Immunity. Cancer Res., May 1, 2006; 66(9): 4904 - 4912. [Abstract] [Full Text] [PDF]
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 O. Saitoh and Y. Nagayama Regulation of Graves' Hyperthyroidism with Naturally Occurring CD4+CD25+ Regulatory T Cells in a Mouse Model Endocrinology, May 1, 2006; 147(5): 2417 - 2422. [Abstract] [Full Text] [PDF]
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Z.-Z. Yang, A. J. Novak, M. J. Stenson, T. E. Witzig, and S. M. Ansell Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma Blood, May 1, 2006; 107(9): 3639 - 3646. [Abstract] [Full Text] [PDF]
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C. Casati, C. Camisaschi, F. Rini, F. Arienti, L. Rivoltini, F. Triebel, G. Parmiani, and C. Castelli Soluble Human LAG-3 Molecule Amplifies the In vitro Generation of Type 1 Tumor-Specific Immunity. Cancer Res., April 15, 2006; 66(8): 4450 - 4460. [Abstract] [Full Text] [PDF]
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). C, CD4/CD8 phenotype of cytotoxic
cells. Individual mice from group I or II in A were
assessed for cytotoxic activity at E:T ratio of 100 after depleting
CD4+ cells, CD8+ cells, or both (designated
CD4- cells, CD8- cells, or
CD4-8- cells, respectively) from the spleen
cells cultured for 7 days with RL
), or anti-
) was added
at various concentrations to the cytotoxicity assay with BALB/c
CD25- cells cultured for 7 days and RL
