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Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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which is endogenously produced by CD3/CD28-stimulated naive T cells, is
involved in induction of the inhibitory activity of myeloid cells.
Importantly, when T cells pre-activated with anti-CD3 Abs were used
as responder cells, the bone marrow- or spleen-derived
Gr-1+ myeloid cells were unable to suppress
CD3/CD28-induced T cell proliferation. Our findings suggest that one
mechanism by which an increased number of immune suppressive
Gr-1+ cells can induce T cell unresponsiveness or immune
tolerance in tumor hosts could be through peroxynitrite production upon
primary T cell activation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been demonstrated previously that cells expressing Gr-1 or Mac-1
myeloid lineage cell markers are involved in T cell hyporesponsiveness
in tumor-bearing mice. CTL activity and T lymphocyte proliferation in
response to alloantigens can be significantly inhibited by
Mac-1-positive cells derived from the spleen of mice bearing colon
carcinoma (13). Direct interaction of T cells with
Mac-1+ cells, derived from mice with large
tumors, can result in the lost of, or significant decrease in, CD3
expression (14). Depletion of Mac-1-positive cells from
the cell suspension can result in the restoration of the CD3
molecule, which is important for signal transduction. Furthermore, the
Gr-1+/Mac-1+ immune
suppressive cell population was recently shown to be involved in
inhibition of CD8+ cell generation in the tumor
host through apoptosis and a contact-dependent mechanism
(15).
Considering the above information, it is essential to know whether immune suppressive myeloid cells can affect primary T cell activation. APC provide at least two signals that are required for T cell activation: a signal via the TCR/CD3 complex that is transmitted upon recognition of Ag and a additional signal(s) delivered through one or more costimulatory cell interactions, like B7-CD28 or LFA-ICAM (16, 17). Only in the presence of the appropriate costimulatory signal does the primed T cell become capable of a productive immune response characterized by proliferation and production of IL-2 (IL-2), differentiation, clonal expansion and effector function (16).
In the current study, we focused our investigation on immature Gr-1+ myeloid cells and their involvement in the regulatory mechanisms of T cell activation and costimulation, as induced through CD3/CD28 ligation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c mice (Taconic Farms, Germantown, NY) between 8 and 12 wk of age were used in the reported experiments. Syngeneic metastatic colon carcinoma was induced in the liver by intrahepatic implantation of 1 x 105 MCA-26 tumor cells, as described previously (18).
Media and reagents
RPMI 1640 medium was supplemented with 10% FCS, 20 mM HEPES, 200 U/ml penicillin, 50 µg/ml streptomycin, 0.05 mM 2-ME, and 2 mM glutamine (all from Sigma, St. Louis, MO). L-NMMA (NG-monomethyl-L-arginine) and MnTBAP (manganese [III] tetrakis [4-benzoic acid] porphyrin) were obtained from Calbiochem (San Diego, CA). Sulfanilamide (N-1-naphtyl)-ethylenediamine, phosphoric acid, sodium nitrite and Percoll were purchased from Sigma. Methyl-[3H]thymidine (5 mCi/mmol) from New Life Science Products (Boston, MA).
Monoclonal Abs
Purified CD3e (clone 145-2C11), CD28 (37.51), Gr-1 (RB6-8C5),
anti-rat IgG2B (Rg7/11.1) mAbs, anti-mouse IFN-,
anti-mouse GM-CSF, anti-mouse/rat TNF-
neutralizing Abs, as
well as purified rat IgG1 and IgG2a isotype control Igs were purchased
from PharMingen (San Diego, CA).
Cell preparation
Mice were sacrificed by cervical dislocation, and their spleens, tibias, and femurs were harvested under sterile conditions. BM cells were obtained by flushing the contents of the mouse femora and tibia with cold PBS using a syringe and a 26-gauge needle in the standard way. Spleen cell (SC) suspensions were prepared by teasing the spleen. Isolated BM and SC were centrifuged for 5 min at 200 x g and resuspended in complete culture medium.
To obtain plastic nonadherent cells, 20 ml of BM or SC (3–4 x 106/ml) were placed in 75 cm2 tissue culture flasks (Costar, Cambridge, MA) and incubated overnight at 37°C in 5% CO2. The next day, the cells were gently washed with medium pre-warmed to 37°C to recover the plastic nonadherent cells, which were then washed and counted.
To separate the isolated plastic nonadherent cells according to their density characteristics, BM or SC were fractionated by centrifugation on a Percoll density gradient as described by Angulo et al. (4). Briefly, 0.5–1 x 108 plastic nonadherent cells were resuspended in 2 ml of 100% Percoll solution. Two milliliters each of 70, 60, 50, and 40% Percoll and 1 ml of HBSS were carefully layered over the cell suspension. After centrifugation at 1800 x g for 30 min, cells were collected from the gradient interfaces. Cells banding between 40 and 50% (<1.063 g/ml) were labeled as fraction (Fr) I; between 50 and 60% (1.063–1.075 g/ml) as Fr. II; and between 60 and 70% (1.075–1.090 g/ml) as Fr. III. After washing, the cells were counted and adjusted to the appropriate concentrations in culture medium.
Myeloid cell-enriched Percoll fractions were depleted of Gr-1+ cells by panning (19). Plastic petri dishes were each coated with 7 ml of secondary anti-rat IgG2b Abs (10 µg/ml; PharMingen). Fractionated BM or SC were incubated with primary Gr-1 Abs in PBS without Ca2+/Mg2+ at a concentration 10 µg/107 cells After washing, the cells were plated onto the precoated petri dishes and incubated for 1 h at 4°C. Nonadherent cells were then collected by gently washing with PBS and used in the appropriate experiments.
In some experiments Fr. II cells, derived from the spleen of MCA-26 tumor-bearing mice were also depleted of T cells by means of complement dependent lysis using anti-CD3 mAbs, as described previously (20).
T cell activation and proliferation assay
For T cell activation experiments, freshly isolated naive splenocytes (2 x 105/well) were cultured in 96-well round-bottom plates in complete culture medium containing soluble, or plate-bound, anti-CD3 (1 µg/ml) and soluble anti-CD28 (5 µg/ml). In some experiments T lymphocytes (1 x 105/well), which were purified from naive spleens using T cell enrichment columns (MTCC-525; R&D Systems, Minneapolis, MN), were used as responder cells instead of bulk splenocytes.
BM or SC fractions, obtained by Percoll fractionation from MCA-26 tumor-bearing mice, were added to the naive splenocytes or purified T cells, activated with CD3 and CD28 Abs. These cell mixtures were cocultured for 72 h at 37°C in 5% CO2. Each well was pulsed with 1 µCi [3H]thymidine for the final 18 h of incubation. Cells were harvested onto filtermates (cat. no. 1450-421, Wallac, Turku, Finland) and radioactivity was measured in a 1450 Microbeta scintillation counter (Wallac). Data are expressed in cpm (mean ± SD of triplicate cultures) or percentage of suppression calculated as follows: % suppression = [(100 - cpm test cells)/cpm control cells] x 100.
MLR
MLR was performed by using C57BL/6 splenocytes (H-2b) as stimulator cells and purified BALB/c T cells (H-2d) as responder cells. Irradiated stimulator cells (5 x 105/well) and responder cells (2 x 105/well) were cultured in 96-well round-bottom plates for 96 h, and [3H]thymidine (1 µCi/well) was added for the final 18 h of incubation. To evaluate the inhibitory activity of the myeloid cell enriched population on MLR, BM or SC fractions were prepared by Percoll fractionation from MCA-26 tumor-bearers and applied in graded doses to MLR.
Flow cytometry
BM or SC (106/tube), which were kept on ice throughout the procedure, were incubated for 30 min with optimal concentrations of Abs. Controls included unstained cells (cell control), samples in which the first step was either omitted (conjugate control), or replaced by an isotype-matched control mAb (mAb control). The cells were analyzed using a FACScan (Becton Dickinson, Mountain View, CA).
NO production
Equal volumes of culture supernatants (100 µl) were mixed with Greiss reagent (21). After a 10-min incubation at room temperature, the absorbance at 550 nm was measured on Spectramax plate reader (Molecular Devices, Sunnyvale, CA). Nitrite concentrations were determined by comparing the absorbance values for the test samples to a standard curve generated by serial dilution of 0.125 mM sodium nitrite.
Statistical analysis
The statistical significance between values was determined by the Student’s t test. All data were expressed as the mean ± SD of triplicates. Probability values >0.05 were considered nonsignificant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Flow cytometric analysis was used to study the frequency of Gr-1
and Mac-1-positive cells in the spleen or BM of mice bearing MCA-26
tumors. While there is a very low number of
Gr-1+/Mac-1+ cells in naive
spleen (2.8 ± 0.3%), the results in Table I
indicate that 43.8 ± 2.5% of the
SC from tumor-bearing animals express both Gr-1 and Mac-1 Ags. BM was
also examined for cells expressing myeloid markers. The percentages of
double positive, as well as single stained, myeloid cells in the bone
marrow of MCA-26 tumor-bearing mice are twice as high as the
percentages seen in cells from naive BM.
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To enrich myeloid cell populations according to their density
characteristics, splenic or BM cell suspensions were depleted of
plastic adherent cells and fractionated using Percoll gradient.
Functional analysis of the fractionated cell populations was conducted
by evaluating their ability to inhibit CD3 or CD3/CD28-induced
activation of naive T cells (Fig. 1).
When naive splenocytes were stimulated by adding anti-CD3 and
anti-CD28 agonistic mAbs, the proliferative response was found to
be inhibited by >90% in the presence of the low density cell Fr. II
derived from BM of tumor-bearing mice (Fig. 1B) as compared
with the response in splenocytes alone. Similarly, Fr. II cells derived
from the spleen of tumor-bearing mice (Fig. 1C) also
strongly inhibited the CD3/CD28-induced proliferation of naive T
cells.
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shows that the immune suppressive
activity of Fr. II cells, derived from BM of MCA-26-bearing mice, was
markedly higher in comparison to the activity of the same cells derived
from naive BM.
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). When purified naive T cells were
stimulated by adding allogeneic irradiated splenocytes, the
proliferative response was found to be inhibited in the presence of the
low density cell fraction (Fr. II) derived from BM of tumor-bearing
mice. Cell Fr. III from the same BM did not display significant
inhibitory activity.
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) that the T cell response can be
restored by depletion of Gr-1-positive cells. Thus, it appears that
Gr-1+ cells are responsible for inhibition of
CD3/CD28-stimulated T cell proliferation in the presence of the immune
suppressive cell fraction derived from BM or spleen of MCA-26
tumor-bearers.
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Because NO is known as the major mediator of natural suppressor
activity (4), we decided to measure the level of nitrites
in cocultures of fractionated tumor-bearer-derived BM (or spleen) cells
and naive SC stimulated with anti-CD3 and anti-CD28 mAbs. In a
representative experiment (Fig. 5A), high nitrite levels were
detected in the culture supernatants of stimulated SC cocultured with
Fr. II cells, i.e., cultures exhibiting a high degree of suppression.
Fr. II cells cultured alone did not generate NO (data not shown). To
test the involvement of NO in the suppression caused by Fr. II cells,
L-NMMA, a competitive inhibitor of inducible NO
synthase (iNOS), was added to the cultures. However, the presence of
L-NMMA did not markedly block the inhibitory
effect of Fr. II cells. In other experiments, no more than 20–25% of
the suppression was reversed when L-NMMA was used
alone (data not shown).
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B shows that immune suppression, mediated by
Gr-1+ cells, can be almost completely reversed in
vitro using a combination of L-NMMA and MnTBAP,
an iNOS inhibitor and superoxide dismutase (SOD) mimetic, respectively.
However, the inhibitory activity of Fr. II cells derived from BM or
spleen of MCA-26 tumor-bearing mice was unaffected when the
proliferation assays were performed in the presence of either
L-NMMA or MnTBAP alone (data not shown). The
presence of MnTBAP in concentrations exceeding 10 µM led to the
impairment of CD3/CD28-induced T cell proliferation in control SC
cultures (data not shown).
IFN- is responsible for induction of the immune suppressive
activity of Gr-1+ cells
The results obtained indicate that to achieve inhibition of T cell
proliferation by Fr. II cells, activation of some inducible enzymes in
cocultured Gr-1+ myeloid cells is required
suggesting a role for T cell-derived cytokine(s), at least in culture.
To investigate the possible role of T cell-released cytokines in the
induction of this inhibitory activity, cocultures were set up in the
presence of various cytokine neutralizing Abs. In a representative
experiment, immune suppression mediated by spleen- or BM-derived
myeloid cells was almost completely abolished in the presence of
neutralizing Abs against IFN- (Fig. 6A), but not in the presence
of isotype control Abs or neutralizing Abs against GM-CSF or TNF-
(Fig. 6C). NO production by myeloid cells was also strongly
inhibited when anti-IFN- mAbs were added (Fig. 6B).
Thus, it appears that the inhibition of CD3/CD28-mediated T cell
proliferation by Fr. II cells is strictly dependent on endogenously
produced IFN-.
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It is important to know whether pre-activated T cells instead of
the primary T cell activation can be inhibited by the immune
suppressive cells derived from MCA-26 tumor-bearing mice. When SC
preincubated with anti-CD3 agonist Ab for 72 h were used as
responder cells (Fig. 7A) in
cocultures with Fr. II cells derived from BM or spleen of
tumor-bearers, no inhibition was observed. In a control experiment
(Fig. 7B); however, BM or SC derived from the same
MCA-26-bearing mice were able to inhibit CD3/CD28-induced primary
activation of naive T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we investigated how Gr-1+
myeloid cells, isolated from MCA-26 tumor-bearing mice and enriched by
fractionation, contribute to inhibition of CD3/CD28-induced T cell
activation. Several findings can be drawn from our experiments. We
demonstrated a quantitative increase in the number of
Gr-1+ cells in both BM and spleen from mice
bearing MCA-26 tumors. These myeloid cells are able to strongly inhibit
the proliferation of naive T cells that have been triggered with
anti-CD3 and anti-CD28 agonistic mAbs. However, the same
suppressive cell population failed to inhibit CD3/CD28-induced
proliferation when the responder T cells were pre-activated with
anti-CD3 mAbs. IFN-, which released from T cells activated by
CD3/CD28, is involved in Gr-1+ cell-mediated
immune suppressive activity. Indeed, neutralization of IFN-, but not
TNF- or GM-CSF, with specific mAbs almost completely abolished the
immune suppressive activity of Gr-1+ cells.
Finally, inhibition of T cell proliferation mediated by myeloid cells
could be prevented by adding a combination of L-NMMA plus
MnTBAP, an iNOS inhibitor and SOD mimetic, respectively, to the
cocultures. These inhibitors could only prevent immune suppression when
used in combination, whereas using either one of them alone failed to
restore CD3/CD28-induced T cell proliferation.
Gr-1 is a myeloid lineage differentiation Ag whose expression on hematopoietic cells can be regulated by certain cytokines, such as GM-CSF and IL-3 (25). These Gr-1-positive cells in murine BM represent a subset consisting mainly of precursors for both granulocytes and monocytes (26). Moreover, in the presence of GM-CSF plus IL-4, Gr-1+/Mac-1+ immune suppressive cells derived from tumor-bearers can be differentiated into fully functional APC in vitro (15). The significant increase in the number of immediate granulocyte-monocyte progenitors in mice bearing large MCA-26 tumors leads to BM of almost complete myeloid composition. As tumor growth progressed, splenomegaly and extramedullary hematopoiesis could be observed (data not shown). However, the exact mechanism by which the growing intrahepatic MCA-26 tumor induces myelopoiesis is not clear. Several cytokines produced by tumors, such as GM-CSF (11, 15), vascular endothelial growth factor (27, 28), and IL-10 (29), have been proposed as candidates for impairment of myelopoiesis in tumor hosts.
In the current study, BM or SC fractions, derived from MCA-26
tumor-bearing mice and enriched for immature myeloid cells, produced a
significant amount of NO in the presence of naive T cells stimulated
with anti-CD3 and anti-CD28 mAbs. This NO production was
inducible and strictly dependent on the presence of endogenous IFN-,
because addition of neutralizing anti-IFN- Abs to the cultures
inhibited accumulation of nitrites in the culture supernatant in a
dose-dependent fashion. However, NO was not primarily responsible for
the observed immune suppression, because adding L-NMMA, a
competitive iNOS inhibitor, to the cultures had no effect on the
impaired T cell proliferation. The presence of MnTBAP, a SOD mimetic,
alone in the culture, also did not restore the impaired T cell
proliferative response to CD3/CD28 stimulation. Only a combination of
these inhibitors was effective in blocking immune suppressive activity.
When taken together, our results indicate that
Gr-1+ myeloid cells become immune suppressive
only in the presence of IFN- due to CD3/28-triggered
primary T cell activation induces releasing of IFN- by T cells. Our
findings point toward a mechanism for negative control of primary T
cell activation if our model for T cell activation, which uses
anti-CD3 and anti-CD28 Abs, is relevant to naturally occurring,
APC-mediated, T cell activation (17). In part, the
physiological relevance of these myeloid immune suppressive cells could
be reflected our data obtained using MLR (Fig. 3).
Regarding the nature of the described inhibitory activity of Gr-1+ myeloid cells under the conditions used in our experiments, it could be caused by peroxynitrite (ONOO-), the reaction product of NO and superoxide (O2). It has been previously demonstrated that a significant portion of the toxic effects attributed to NO is due to the generation of ONOO- (30). Peroxynitrite is a powerful oxidant that can inhibit T cell activation and proliferation by impairment of tyrosine phosphorylation and apoptotic death (31). Our results suggest that production of reactive nitrogen and oxygen intermediates by myeloid cells could play a major role in the impairment of T cell activation upon CD28 costimulation. It is not surprising that immature myeloid cells can generate reactive oxygen species (ROS) and nitrogen species, because ROS is involved in signal transduction of hematopoietic growth factors (32), whereas NO is involved in mechanisms of differentiation and maturation of myeloid cells in BM (33, 34).
It is known that costimulation through B7-CD28 interaction in the
presence of TCR signaling induces full T cell activation. However, our
data clearly indicate that when CD3/CD28-induced T cell activation
occurs in the presence of Gr-1+ natural
suppressor cells, T cells become deactivated or tolerized. This
deactivation of T cells, at least in vitro, can be achieved upon
CD3/CD28 triggering, and IFN- plays a critical role in this
deactivation. We suggest that the presence of immune suppressive
myeloid cells in secondary lymphoid organs, such as spleen, can down
modulate, or even prevent, development of an adaptive T cell antitumor
immune response. This type of feedback mechanism could also play an
important role in the development of tolerance, one of the means by
which a growing tumor may escape the T cell immune response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shu-Hsia Chen, Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 13-02, New York, NY 10029-6574.
3 Abbreviations used in this paper: BM, bone marrow; MCA-26, murine colon carcinoma; SC, spleen cell; iNOS, inducible NO synthase; L-NMMA, NG-monomethyl-L-arginine; MnTBAP, manganese [III] tetrakis [4-benzoic acid] porphyrin; SOD, superoxide dismutase; Fr., fraction.
Received for publication December 16, 1999. Accepted for publication May 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain of T cell receptor complex and antigen-specific T-cell responses. Proc. Natl. Acad. Sci. USA 93:1319.
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Y. Huang, X. Chen, M. M. Dikov, S. V. Novitskiy, C. A. Mosse, L. Yang, and D. P. Carbone Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF Blood, July 15, 2007; 110(2): 624 - 631. [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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J. Vieweg, Z. Su, P. Dahm, and S. Kusmartsev Reversal of Tumor-Mediated Immunosuppression Clin. Cancer Res., January 15, 2007; 13(2): 727s - 732s. [Abstract] [Full Text] [PDF]
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A. Minguela, S. Pastor, W. Mi, J. A. Richardson, and E. S. Ward Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon {gamma} J. Immunol., January 1, 2007; 178(1): 134 - 144. [Abstract] [Full Text] [PDF]
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A. V. Ezernitchi, I. Vaknin, L. Cohen-Daniel, O. Levy, E. Manaster, A. Halabi, E. Pikarsky, L. Shapira, and M. Baniyash TCR {zeta} Down-Regulation under Chronic Inflammation Is Mediated by Myeloid Suppressor Cells Differentially Distributed between Various Lymphatic Organs J. Immunol., October 1, 2006; 177(7): 4763 - 4772. [Abstract] [Full Text] [PDF]
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N. Mirza, M. Fishman, I. Fricke, M. Dunn, A. M. Neuger, T. J. Frost, R. M. Lush, S. Antonia, and D. I. Gabrilovich All-trans-Retinoic Acid Improves Differentiation of Myeloid Cells and Immune Response in Cancer Patients. Cancer Res., September 15, 2006; 66(18): 9299 - 9307. [Abstract] [Full Text] [PDF]
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 I. Kryczek, L. Zou, P. Rodriguez, G. Zhu, S. Wei, P. Mottram, M. Brumlik, P. Cheng, T. Curiel, L. Myers, et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma J. Exp. Med., April 17, 2006; 203(4): 871 - 881. [Abstract] [Full Text] [PDF]
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B. Huang, P.-Y. Pan, Q. Li, A. I. Sato, D. E. Levy, J. Bromberg, C. M. Divino, and S.-H. Chen Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host Cancer Res., January 15, 2006; 66(2): 1123 - 1131. [Abstract] [Full Text] [PDF]
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S. K. Bunt, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression J. Immunol., January 1, 2006; 176(1): 284 - 290. [Abstract] [Full Text] [PDF]
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H. Fujigaki, K. Saito, F. Lin, S. Fujigaki, K. Takahashi, B. M. Martin, C. Y. Chen, J. Masuda, J. Kowalak, O. Takikawa, et al. Nitration and Inactivation of IDO by Peroxynitrite J. Immunol., January 1, 2006; 176(1): 372 - 379. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, S. Nagaraj, and D. I. Gabrilovich Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells J. Immunol., October 1, 2005; 175(7): 4583 - 4592. [Abstract] [Full Text] [PDF]
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B. Larrivee, I. Pollet, and A. Karsan Activation of Vascular Endothelial Growth Factor Receptor-2 in Bone Marrow Leads to Accumulation of Myeloid Cells: Role of Granulocyte-Macrophage Colony-Stimulating Factor J. Immunol., September 1, 2005; 175(5): 3015 - 3024. [Abstract] [Full Text] [PDF]
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J. Honeychurch, M. J. Glennie, and T. M. Illidge Cyclophosphamide Inhibition of Anti-CD40 Monoclonal Antibody-Based Therapy of B Cell Lymphoma Is Dependent on CD11b+ Cells Cancer Res., August 15, 2005; 65(16): 7493 - 7501. [Abstract] [Full Text] [PDF]
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S. P. Zehntner, C. Brickman, L. Bourbonniere, L. Remington, M. Caruso, and T. Owens Neutrophils That Infiltrate the Central Nervous System Regulate T Cell Responses J. Immunol., April 15, 2005; 174(8): 5124 - 5131. [Abstract] [Full Text] [PDF]
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 M.-B. Voisin, D. Buzoni-Gatel, D. Bout, and F. Velge-Roussel Both Expansion of Regulatory GR1+ CD11b+ Myeloid Cells and Anergy of T Lymphocytes Participate in Hyporesponsiveness of the Lung-Associated Immune System during Acute Toxoplasmosis Infect. Immun., September 1, 2004; 72(9): 5487 - 5492. [Abstract] [Full Text] [PDF]
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M. J. Skeen, M. M. Freeman, and H. K. Ziegler Changes in peritoneal myeloid populations and their proinflammatory cytokine expression during infection with Listeria monocytogenes are altered in the absence of {gamma}/{delta} T cells J. Leukoc. Biol., July 1, 2004; 76(1): 104 - 115. [Abstract] [Full Text] [PDF]
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Q. Li, P.-Y. Pan, P. Gu, D. Xu, and S.-H. Chen Role of Immature Myeloid Gr-1+ Cells in the Development of Antitumor Immunity Cancer Res., February 1, 2004; 64(3): 1130 - 1139. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, Y. Nefedova, D. Yoder, and D. I. Gabrilovich Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species J. Immunol., January 15, 2004; 172(2): 989 - 999. [Abstract] [Full Text] [PDF]
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J. A. Perry, A. Rush, R. J. Wilson, C. S. Olver, and A. C. Avery Dendritic Cells from Malaria-Infected Mice Are Fully Functional APC J. Immunol., January 1, 2004; 172(1): 475 - 482. [Abstract] [Full Text] [PDF]
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M. Terabe, S. Matsui, J.-M. Park, M. Mamura, N. Noben-Trauth, D. D. Donaldson, W. Chen, S. M. Wahl, S. Ledbetter, B. Pratt, et al. Transforming Growth Factor-{beta} Production and Myeloid Cells Are an Effector Mechanism through Which CD1d-restricted T Cells Block Cytotoxic T Lymphocyte-mediated Tumor Immunosurveillance: Abrogation Prevents Tumor Recurrence J. Exp. Med., December 1, 2003; 198(11): 1741 - 1752. [Abstract] [Full Text] [PDF]
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C. Melani, C. Chiodoni, G. Forni, and M. P. Colombo Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity Blood, September 15, 2003; 102(6): 2138 - 2145. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, F. Cheng, B. Yu, Y. Nefedova, E. Sotomayor, R. Lush, and D. Gabrilovich All-trans-Retinoic Acid Eliminates Immature Myeloid Cells from Tumor-bearing Mice and Improves the Effect of Vaccination Cancer Res., August 1, 2003; 63(15): 4441 - 4449. [Abstract] [Full Text] [PDF]
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S. Kusmartsev and D. I. Gabrilovich Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species J. Leukoc. Biol., August 1, 2003; 74(2): 186 - 196. [Abstract] [Full Text] [PDF]
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M. Dupuis, M. de Jesus Ibarra-Sanchez, M. L. Tremblay, and P. Duplay Gr-1+ Myeloid Cells Lacking T Cell Protein Tyrosine Phosphatase Inhibit Lymphocyte Proliferation by an IFN-{gamma}- and Nitric Oxide-Dependent Mechanism J. Immunol., July 15, 2003; 171(2): 726 - 732. [Abstract] [Full Text] [PDF]
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Y. Liu, J. A. Van Ginderachter, L. Brys, P. De Baetselier, G. Raes, and A. B. Geldhof Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells J. Immunol., May 15, 2003; 170(10): 5064 - 5074. [Abstract] [Full Text] [PDF]
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V. Bronte, P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. Sutter, et al. IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J. Immunol., January 1, 2003; 170(1): 270 - 278. [Abstract] [Full Text] [PDF]
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A. B. Geldhof, J. A. Van Ginderachter, Y. Liu, W. Noel, G. Raes, and P. De Baetselier Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation Blood, December 1, 2002; 100(12): 4049 - 4058. [Abstract] [Full Text] [PDF]
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 O. Goni, P. Alcaide, and M. Fresno Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1+)CD11b+ immature myeloid suppressor cells Int. Immunol., October 1, 2002; 14(10): 1125 - 1134. [Abstract] [Full Text] [PDF]
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A. Mencacci, C. Montagnoli, A. Bacci, E. Cenci, L. Pitzurra, A. Spreca, M. Kopf, A. H. Sharpe, and L. Romani CD80+Gr-1+ Myeloid Cells Inhibit Development of Antifungal Th1 Immunity in Mice with Candidiasis J. Immunol., September 15, 2002; 169(6): 3180 - 3190. [Abstract] [Full Text] [PDF]
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A. Mazzoni, V. Bronte, A. Visintin, J. H. Spitzer, E. Apolloni, P. Serafini, P. Zanovello, and D. M. Segal Myeloid Suppressor Lines Inhibit T Cell Responses by an NO-Dependent Mechanism J. Immunol., January 15, 2002; 168(2): 689 - 695. [Abstract] [Full Text] [PDF]
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E. A. Patton, A. C. La Flamme, J. A. Pedras-Vasoncelos, and E. J. Pearce Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis Infect. Immun., January 1, 2002; 70(1): 177 - 184. [Abstract] [Full Text] [PDF]
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L. I. Terrazas, K. L. Walsh, D. Piskorska, E. McGuire, and D. A. Harn Jr. The Schistosome Oligosaccharide Lacto-N-neotetraose Expands Gr1+ Cells That Secrete Anti-inflammatory Cytokines and Inhibit Proliferation of Naive CD4+ Cells: A Potential Mechanism for Immune Polarization in Helminth Infections J. Immunol., November 1, 2001; 167(9): 5294 - 5303. [Abstract] [Full Text] [PDF]
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O. Atochina, T. Daly-Engel, D. Piskorska, E. McGuire, and D. A. Harn A Schistosome-Expressed Immunomodulatory Glycoconjugate Expands Peritoneal Gr1+ Macrophages That Suppress Naive CD4+ T Cell Proliferation Via an IFN-{gamma} and Nitric Oxide-Dependent Mechanism J. Immunol., October 15, 2001; 167(8): 4293 - 4302. [Abstract] [Full Text] [PDF]
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M. J. Dobrzanski, J. B. Reome, and R. W. Dutton Role of Effector Cell-Derived IL-4, IL-5, and Perforin in Early and Late Stages of Type 2 CD8 Effector Cell-Mediated Tumor Rejection J. Immunol., July 1, 2001; 167(1): 424 - 434. [Abstract] [Full Text] [PDF]
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E. Y. Woo, C. S. Chu, T. J. Goletz, K. Schlienger, H. Yeh, G. Coukos, S. C. Rubin, L. R. Kaiser, and C. H. June Regulatory CD4+CD25+ T Cells in Tumors from Patients with Early-Stage Non-Small Cell Lung Cancer and Late-Stage Ovarian Cancer Cancer Res., June 1, 2001; 61(12): 4766 - 4772. [Abstract] [Full Text] [PDF]
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B. Pelaez, J. A. Campillo, J. A. Lopez-Asenjo, and J. L. Subiza Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism J. Immunol., June 1, 2001; 166(11): 6608 - 6615. [Abstract] [Full Text] [PDF]
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D. I. Gabrilovich, M. P. Velders, E. M. Sotomayor, and W. M. Kast Mechanism of Immune Dysfunction in Cancer Mediated by Immature Gr-1+ Myeloid Cells J. Immunol., May 1, 2001; 166(9): 5398 - 5406. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, Naive splenocytes only; 
, naive splenocytes plus
cell Fr. II; 
, naive splenocytes plus cell Fr. III.
is stimulator cells alone (irradiated C57BL/6
splenocytes); 
is responder plus stimulator cells; 
is responder
plus stimulator cells plus cell Fr. III from TB BM; and 
