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Immunobiology Department, DNAX Research Institute of Molecular Immunology and Cellular Biology, Palo Alto, CA 94304
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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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- or
IL-4-induced class II MHC expression on monocytes, dendritic cells, and
Langerhans cells (2, 8, 9). It has also been shown that IL-10, in the
absence of professional APC, has direct effects on
CD4+ T by suppressing IL-2 and TNF-
secretion (10, 11). IL-10 also strongly reduces the proliferation and cytokine
production of alloreactive T cells in MLR. Moreover, the generation of
allospecific cytotoxic activity is inhibited by IL-10 (12). We have
recently shown that in addition to inhibiting Ag-specific responses,
IL-10 induces long lasting Ag-specific anergy in human CD4+
T cells (13).
On the other hand, IL-10 also has immunostimulatory effects on B and T
cells. IL-10 augments the proliferation and the differentiation into
Ab-secreting cells of splenic activated B cells (14, 15). IL-10 also
rescues T cells from apoptotic cell death (16). In addition, it has
been reported that IL-10 enhances the proliferative responses of murine
thymocytes (17) and IL-2- and IL-4-driven proliferation of murine
CD8+ T cells in vitro (18). IL-10 also has
immunostimulatory effects in vivo. Injection of high doses of IL-10
(200 µg/mice/day) in mice with graft-vs-host disease, due to both
major and minor MHC disparities, resulted in a exacerbation of the
disease, which was probably mediated by IFN- production (19). In
addition, in an IL-10 transgenic model, IL-10 enhances the accumulation
of CD8+ T cells in the pancreata (20), leading to an
earlier onset of diabetes in nonobese diabetic mice (21). These data
suggest that IL-10 may have differential effects on CD4+
and CD8+ T cells.
In the present study, we demonstrate that IL-10 has a dual effect on human CD8+ T cells. IL-10 suppresses the proliferative responses and induces alloantigen-specific unresponsiveness in human CD8+ T cells activated in the presence of professional APC. These effects are indirect and are mediated through inhibition of the costimulatory functions of APC. In contrast, IL-10 has no direct inhibitory effect on the proliferation of CD8+ T cells activated via their TCR in the absence of APC and displays a growth-promoting activity on activated CD8+ T cells in combination with low doses of IL-2.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC were isolated on Ficoll-Hypaque. CD8+ T cells were purified by negative selection using a mixture of Abs directed against non-CD8+ cells: CD4, CD14, CD16, CD19, CD20, CD56, and HLA-DR. Cells were incubated with saturating amounts of Abs for 20 min at 4°C. After washing, Dynabeads (Dynal, Oslo, Norway) were added at a ratio of 10 beads/target cell and incubated for 1 h at 4°C. Beads and contaminating cells were removed by magnetic field. The remaining cells were resuspended with the same amount of beads, and a second incubation period for 1 h at 4°C was performed. After removal of contaminating cells, CD8+ T cells were analyzed by cytofluorometry and showed >90 to 95% positive. In some experiments, CD8+ T cells were purified (>98% pure) by positive selection using magnetic beads coated with anti-CD8 mAb according to the manufacturer’s instructions (Dynal). Monocytes were purified by negative selection using the procedure described above with an Ab mixture containing CD2, CD3, CD8, CD16, CD19, CD20, and CD56. These monocytes were >95% CD14+ as shown by cytofluorometry.
Reagents
Purified recombinant IL-10 was provided by Schering-Plough Research Institute (Bloomfield, NJ), and rIL-2 was a gift from Dr. S. Menon (DNAX Research Institute, Palo Alto, CA). The anti-CD3 mAb SPV-T3 (22), anti-IL-2 (BG-5), anti-IL-2R (B-B10) (23) or anti-IL-10 (9D7) mAbs were previously described. Nonconjugated, phycoerythrin-conjugated, or FITC-conjugated CD2, CD3, CD4, CD8, CD14, CD16, CD19, CD20, CD28, CD54, CD56, CD80, HLA class I, HLA-DR, and controls mAbs of the appropriate isotypes were purchased from Becton Dickinson (Mountain View, CA) except for CD86 (PharMingen, San Diego, CA).
Proliferation assays
All proliferation assays were conducted in Yssel’s medium (24) supplemented with 10% FCS and 1% human serum. MLR were performed by stimulating purified CD8+ T cells (105 cells/well) with purified irradiated (4000 rad) monocytes (105 cells/well) in 200-µl round-bottom 96-well plates (Linbro, ICN, Aurora, OH). CD8+ T cell proliferation was measured after 5 days of incubation at 37°C and 5% CO2 and a subsequent 12-h pulse with [3H]TdR, after which the cells were harvested as described (25).
For plate-bound anti-CD3 mAbs activation, 100 ng/ml of anti-CD3 mAbs diluted in 0.1 M Tris buffer, pH 9.5, were incubated for 1 week at 4°C in flat-bottom 96-well plates. After the plates were washed, CD8+ T cells were added at a concentration of 5 x 104 cells/well. CD8+ T cell proliferation was measured after 3 days of incubation followed by a 12-h pulse with [3H]TdR. All tests were conducted in triplicate.
Induction of unresponsiveness
Ag-specific unresponsiveness was induced by culturing CD8+ T cells at 106 cells/ml with purified irradiated allogeneic monocytes (106 cells/ml), in the presence of IL-10 (100 U/ml) in 24-well plates. After 10 days, cells were collected, layered on a Ficoll gradient, and centrifuged for 30 min at 1200 rpm to remove dead cells. The viable cells were collected from the interface, washed twice, and restimulated at 5 x 105 cells/ml with irradiated allogeneic monocytes (5 x 105 cell/ml) from the same donor in 96-well plates.
Immunofluorescence analysis
Cell surface Ag expression on monocytes incubated with IL-10 for different period times was determined by immunofluorescence. Monocytes (105) were labeled with phycoerythrin- or FITC-conjugated mAbs. Cells were incubated with the appropriate Ab for 30 min at 4°C in PBS with 0.1% BSA and 0.02 mM NaN3. After three washes, the labeled cell samples were analyzed on a FACScan (Becton Dickinson, San Jose, CA).
Cytotoxicity assays
The cytotoxic activity was measured as described previously (12). In brief, 2 x 103 51Cr-labeled target cells (PHA blasts) were incubated with graded numbers of CD8+ T effector cells in 200 µl of medium in round-bottom microtiter plates (Linbro, ICN). The plates were centrifuged and incubated for 4 h at 37°C. The supernatants were harvested with a Skatron (Sterling, VA) harvesting system and counted in a gamma counter. All test samples were measured in triplicate. The percentage of specific 51Cr release was calculated as described (12).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-10 inhibited in a dose-dependent manner the proliferation of
purified CD8+ T cells in response to purified
allogeneic irradiated monocytes in primary MLR. Strong inhibitory
effects were observed at IL-10 concentrations as low as 10 U/ml,
whereas maximal inhibition was observed at 100 U/ml (Fig. 1
A). These inhibitory
effects of IL-10 on the proliferation of purified CD8+ T
cells were completely restored by exogenous IL-2 (Fig. 1A).
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B) even after addition of up to 10,000 U/ml of
IL-10 (Fig. 1A). These results suggest that the
inhibitory effect of IL-10 on alloantigen-specific CD8+ T
cell proliferation is indirect and is caused by inhibition of the APC
function of monocytes. This was confirmed by the observation that IL-10
inhibited specifically the costimulatory functions of autologous
monocytes on anti-CD3 mAb-induced proliferation of CD8+
T cells (Fig. 1B). Moreover, the inhibitory effect of
IL-10 was observed only after preincubating with IL-10 allogeneic
monocytes before coculture (Fig. 1C). No inhibition
was observed after preincubation of CD8+ T cells with IL-10
(Fig. 1C). Finally, transwell experiments where
CD8+ T cells were stimulated with immobilized anti-CD3
mAb and cocultured with autologous monocytes either on close contact or
separated by a semipermeable membrane have shown that IL-10 inhibited
both the secretion of stimulatory monokines and costimulatory cell
surface molecules (Fig. 1D) and did not induced the
secretion of a suppressive factor. IL-10 induces Ag-specific unresponsiveness in CD8+ T cells
Recently, we showed that CD4+ T cells stimulated
by alloantigens in the presence of IL-10 for prolonged periods of time
failed to respond when restimulated with the same specific Ag (13). To
analyze whether IL-10 had the same effect on CD8+ T cells,
purified CD8+ T cells were stimulated by allogeneic
monocytes in the presence or absence of IL-10 for 10 days. After this
culture period, alloantigen-stimulated CD8+ T cells were
restimulated with the same allogeneic irradiated monocytes in secondary
MLR or with third-party allogeneic monocytes in primary MLR.
CD8+ T cells that had been cultured in the absence of IL-10
proliferated strongly in response to the allogeneic stimuli (Fig. 2). In contrast, CD8+ T cells
activated and incubated in the presence of IL-10 showed a strong
reduction in their secondary proliferative responses to the same
allogeneic monocytes (Fig. 2). However, they retained their capacity to
proliferate to third-party alloantigens in primary MLR (Fig. 2).
Comparable levels of cell death were observed in both culture
conditions, and comparable cell numbers were harvested at termination
of the assays (data not shown). These results indicate that IL-10
induces an Ag-specific unresponsive state in CD8+ T cells
in a manner similar to that described for CD4+ T cells
(13).
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To determine whether the induction of the unresponsive state in
CD8+ T cells following activation by allogeneic
monocytes in the presence of IL-10 was due to a down-regulation of
costimulatory signals, monocytes were incubated with IL-10 for
different time periods, and the expression of costimulatory cell
surface molecules was analyzed. Flow cytometric analysis by direct
staining with a mAb against nonpolymorphic determinants of HLA class I
indicated that IL-10 down-regulates HLA class I expression, but to a
lesser extent than HLA class II expression (Fig. 3). In addition, IL-10 down-regulated the
expression of the costimulatory molecules CD80 and CD86 and the
adhesion molecule ICAM-1 (Fig. 3), as demonstrated previously (6, 26).
However, no change in CD58 expression was observed (Fig. 3).
Collectively, these results indicate that IL-10-induced
alloantigen-specific unresponsiveness in CD8+ T cells is
indirectly mediated by APC and is associated with down-regulation of
costimulatory molecules and to a lesser extent of class I MHC
Ags.
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To test whether IL-10 also inhibits the generation of alloantigen
specific cytotoxic T cells, purified CD8+ T cells were
stimulated with purified allogeneic monocytes on primary MLR in the
presence of different doses of IL-10. Five days later, the
CD8+ T cells were collected and used as effector cells
against autologous or allogeneic PHA blasts. CD8+ CTL
killed the allogeneic T-cell blasts in a dose-dependent manner (Fig. 4), whereas no significant cytotoxic
activities were observed against autologous T cell blasts (not shown).
The alloantigen-specific cytotoxicity by CD8+ T cells that
had been activated in the presence of IL-10 was strongly reduced (Fig. 4). Significant inhibition of specific cytotoxicity was already
observed at 10 U/ml of IL-10, whereas >90% reduction in cytotoxic
activity was obtained at an IL-10 concentration of 100 U/ml.
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To determine whether IL-10 has direct effects on the
proliferation of human CD8+ T cells, human purified
CD8+ T cells were stimulated with cross-linked anti-CD3
mAb in the presence of anti-IL-2 or anti-IL-2R mAbs or both and
IL-10. Anti-IL-2 mAbs strongly inhibited the proliferation of purified
CD8+ T cells activated with anti-CD3 (Fig. 5A). Similar results
were obtained by adding anti-IL-2R -chain (CD25) mAbs or both
Abs, demonstrating that this proliferation is IL-2 dependent.
Interestingly, addition of high concentrations of IL-10 (100 U/ml)
restored CD8+ T cell proliferation, indicating that IL-10
may act as a growth factor for CD8+ T cells in the absence
of IL-2. However, the proliferation of CD8+ T cells
activated with immobilized anti-CD3 mAbs in the presence of
saturating amounts of anti-IL-2 and/or anti-IL-2 R mAbs was
never completely blocked even in the presence of a blocking
anti-IL-10 mAb (Fig. 5A), suggesting that IL-10
may act only as a cofactor for CD8+ T cell proliferation in
the presence of low concentrations of IL-2. To test this possibility,
IL-10 was added to CD8+ T cells preactivated by immobilized
anti-CD3 mAb and cultured in the presence of IL-2. IL-10 enhances
IL-2 driven proliferation of preactivated CD8+ T cells,
especially when low IL-2 and high IL-10 concentrations were used (Fig. 5B). IL-10 alone, in the absence of IL-2,
consistently failed to induce significant levels of CD8+ T
cell proliferation. This is because CD8+ T cells that have
been preactivated for 5 days failed to produce detectable amounts of
IL-2 (not shown). These data suggest that IL-10 synergizes with a low
concentration of IL-2 in enhancing CD8+ T cell
proliferation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
IL-1, IL-1ß, IL-6) and chemokines (IL-8, MIP-1) by activated
human monocytes (3, 29). These suppressive and antiinflammatory
activities suggest a potential clinical use of IL-10 as a potent
immunosuppressant in allogeneic transplantation and autoimmune
diseases. The results of experimental (30) and clinical studies (31)
support this hypothesis. High levels of endogenous IL-10 were observed
in successfully transplanted SCID patients in whom tolerance was
established (25). Furthermore, a correlation between high survival
rates and high concentrations of endogenous IL-10 has been described in
patients with malignancies transplanted with allogeneic bone marrow
(32). These findings suggest that the concentrations of IL-10 may be
important to prevent graft-vs-host disease and determine the outcome of
the transplant. Moreover, in vivo injection of IL-10 in humans has been
shown to have inhibitory effects on T cells and to suppress the
production of the proinflammatory cytokines TNF- and IL-1ß
(31). However, other in vivo studies have shown that IL-10 was not able to suppress an immune response. IL-10 was not able to prevent graft-vs-host disease (33) and in some situations even had exacerbating effects (19) when administered either at the same time as or after bone marrow transplant. In addition, IL-10 transgenically expressed in ß cells did not prevent or modify rejection of allogeneic fetal pancreata or adult ß cells (34). The discrepancy between these in vivo effects of IL-10 in humans and mice may be due to the fact that under certain conditions IL-10 may act as an immunostimulant instead of as an immunosuppressant. In this study, we demonstrate that IL-10 has differential immunosuppressive or stimulatory effects on CD8+ T cells depending on their stage of activation.
IL-10 decreases proliferation and cytotoxic functions of
CD8+ T cells when added before or at the time of
activation. Moreover, human CD8+ T cells activated by
allogeneic monocytes in the presence of IL-10 for 10 days were rendered
unresponsive to a secondary stimulation with the same Ag. However,
these T cells proliferated normally in response to third-party
alloantigens. Similar results have been obtained with CD4+
T cells (13). In contrast to the results obtained with CD4+
T cells, IL-10 failed to decrease the proliferative responses of
CD8+ T cells induced by activation with cross-linked
anti-CD3 mAbs. Furthermore, no unresponsive state was achieved
after incubation of CD8+ T cells with IL-10 for 10 days
following stimulation with cross-linked CD3 mAb. Taken together, these
data indicate that T cell unresponsiveness induced by IL-10 is not
related to a direct effect on CD8+ T cells but to
inhibition of Ag-presenting and accessory function of monocytes, which
is associated with down-regulation of monokine secretion and expression
of class I MHC and accessory molecules on these cells (Figs. 1 and 3).
It is well established that mouse CD4+ and CD8+ T cell clones lose their ability to proliferate and to secrete IL-2 and that they become anergic when stimulated with fixed APC (35, 36). Additional experiments have shown that these activation conditions allow TCR engagement in the absence of the costimulatory signals mediated by APC. Indeed, it has been shown, mostly for CD4+ T cell clones, that anergy is induced when T cells are stimulated by APC in which the costimulatory signals are blocked by Abs directed against key costimulatory molecules such as CD80, CD86, CD54, or CD58 (37, 38, 39). However, CD4+ and CD8+ T cells may have different requirements for costimulation and induction of anergy, which could explain the differences in their susceptibility to be rendered unresponsive by IL-10. In CD4+ T cells expressing CD80, costimulatory signals provided by T-T cell interaction can be sufficient to reach the threshold required to induce cell proliferation after CD3 cross-linking (40). Il-10-mediated down-regulation of these costimulatory signals provided by CD4+ T cells may explain the observed anergic state of CD4+ T cells. CD8+ T cells seem to be less dependent on costimulatory signals since these cells could be induced to proliferate in response to stimulation by fibroblasts, whereas CD4+ T cells failed to do so. Therefore, it may be speculated that because of this relative independence of costimulatory signals, IL-10 is not effective in inhibiting proliferation and inducing unresponsiveness of purified CD8+ T cells activated in the absence of professional APC.
The failure of CD8+ T cells to proliferate in response to
allogeneic monocytes in the presence of IL-10 correlated with a reduced
capability of these CD8+ T cells to lyse allogeneic target
cells. These results may reflect a decrease in the frequency of
effector cells due to IL-10 inhibition of T cell activation in primary
MLR. Alternatively, it is possible that a functional impairment of the
CD8+ T cells is induced by in vitro priming in the presence
of IL-10, resulting in lack of both proliferation and cytotoxic
activity. This latter hypothesis is supported by a recent study in
which it is shown that IL-10 is responsible for the lack of cytotoxic
activity by specific CD8+ T cell clones and that blocking
of endogenous IL-10 production restored the cytotoxic activity (41). In
contrast to the suppressive effects of IL-10 on the proliferative and
cytotoxic responses of CD8+ T cells activated in the
presence of APC, IL-10 enhances the proliferation of preactivated human
CD8+ T cells induced by IL-2. Therefore, IL-10 has a
stimulatory function on activated CD8+ T cells by acting as
a cofactor for IL-2. The mechanism by which IL-10 acts as a cofactor
for IL-2 in promoting the proliferation of activated CD8+ T
cells is unclear. However, in contrast to a previous report on
CD4+ T cells (42), IL-10 does not enhance the IL-2R
-chain on activated CD8+ T cells (not shown). Moreover,
the observation that IL-10 sustains CD8+ T cell
proliferation in the presence of an anti-IL-2R mAb suggests that
the synergy between IL-10 and IL-2 is not mediated through IL-2R
expression.
Overall, these data suggest that IL-10 may inhibit or stimulate CD8+ T cells, depending on the time at which the cells are exposed to IL-10. These differential effects may explain some discrepancies observed in vivo in different experimental models. It can be hypothesized that IL-10 is effective in vivo in preventing and inhibiting undesirable immune responses mediated by CD8+ T cells, if present at the same time as Ag exposure, but that it fails to suppress ongoing responses mediated by activated CD8+ T cells. This should be taken into account for the future potential clinical use of IL-10 in autoimmune diseases and organ transplantation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hervé Groux, DNAX Research Institute of Molecular Immunology and Cellular Biology, 901 California Avenue, Palo Alto CA 94304-1104. E-mail address:
3 Current address: Novartis Research Institute, Brunner Strasse 59, A-1235 Wien, Austria.
4 Current address: University of Torino, Department of Pediatrics-Immunology Unit, Regina Margherita Children’s Hospital, Piazza Polonia 94, 10126 Turin, Italy.
Received for publication September 11, 1997. Accepted for publication December 5, 1997.
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L. Frasca, C. Scotta, G. Lombardi, and E. Piccolella Human Anergic CD4+ T Cells Can Act as Suppressor Cells by Affecting Autologous Dendritic Cell Conditioning and Survival J. Immunol., February 1, 2002; 168(3): 1060 - 1068. [Abstract] [Full Text] [PDF]
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S.-i. Fujii, K. Shimizu, T. Shimizu, and M. T. Lotze Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ Blood, October 1, 2001; 98(7): 2143 - 2151. [Abstract] [Full Text] [PDF]
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A. Wakkach, F. Cottrez, and H. Groux Differentiation of Regulatory T Cells 1 Is Induced by CD2 Costimulation J. Immunol., September 15, 2001; 167(6): 3107 - 3113. [Abstract] [Full Text] [PDF]
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 L. Sen, Y.-S. Hong, H. Luo, G. Cui, and H. Laks Efficiency, efficacy, and adverse effects of adenovirus- vs. liposome-mediated gene therapy in cardiac allografts Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1433 - H1441. [Abstract] [Full Text] [PDF]
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M. Deckert, S. Soltek, G. Geginat, S. Lutjen, M. Montesinos-Rongen, H. Hof, and D. Schluter Endogenous Interleukin-10 Is Required for Prevention of a Hyperinflammatory Intracerebral Immune Response in Listeria monocytogenes Meningoencephalitis Infect. Immun., July 1, 2001; 69(7): 4561 - 4571. [Abstract] [Full Text] [PDF]
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S. Kawamoto, Y. Nitta, F. Tashiro, A. Nakano, E. Yamato, H. Tahara, K. Tabayashi, and J.-i. Miyazaki Suppression of Th1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10 Int. Immunol., May 1, 2001; 13(5): 685 - 694. [Abstract] [Full Text] [PDF]
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M. K. Levings, R. Sangregorio, F. Galbiati, S. Squadrone, R. de Waal Malefyt, and M.-G. Roncarolo IFN-{{alpha}} and IL-10 Induce the Differentiation of Human Type 1 T Regulatory Cells J. Immunol., May 1, 2001; 166(9): 5530 - 5539. [Abstract] [Full Text] [PDF]
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N. S. Ostlie, P. I. Karachunski, W. Wang, C. Monfardini, M. Kronenberg, and B. M. Conti-Fine Transgenic Expression of IL-10 in T Cells Facilitates Development of Experimental Myasthenia Gravis J. Immunol., April 15, 2001; 166(8): 4853 - 4862. [Abstract] [Full Text] [PDF]
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J. L. Croxford, M. Feldmann, Y. Chernajovsky, and D. Baker Different Therapeutic Outcomes in Experimental Allergic Encephalomyelitis Dependant Upon the Mode of Delivery of IL-10: A Comparison of the Effects of Protein, Adenoviral or Retroviral IL-10 Delivery into the Central Nervous System J. Immunol., March 15, 2001; 166(6): 4124 - 4130. [Abstract] [Full Text] [PDF]
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B. Balasa, A. La Cava, K. Van Gunst, L. Mocnik, D. Balakrishna, N. Nguyen, L. Tucker, and N. Sarvetnick A Mechanism for IL-10-Mediated Diabetes in the Nonobese Diabetic (NOD) Mouse: ICAM-1 Deficiency Blocks Accelerated Diabetes J. Immunol., December 15, 2000; 165(12): 7330 - 7337. [Abstract] [Full Text] [PDF]
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F. N. Lauw, D. Pajkrt, C. E. Hack, M. Kurimoto, S. J. H. van Deventer, and T. van der Poll Proinflammatory Effects of IL-10 During Human Endotoxemia J. Immunol., September 1, 2000; 165(5): 2783 - 2789. [Abstract] [Full Text] [PDF]
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A. D. Santin, P. L. Hermonat, A. Ravaggi, S. Bellone, S. Pecorelli, J. J. Roman, G. P. Parham, and M. J. Cannon Interleukin-10 Increases Th1 Cytokine Production and Cytotoxic Potential in Human Papillomavirus-Specific CD8+ Cytotoxic T Lymphocytes J. Virol., May 15, 2000; 74(10): 4729 - 4737. [Abstract] [Full Text]
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A. Knappe, S. Hör, S. Wittmann, and H. Fickenscher Induction of a Novel Cellular Homolog of Interleukin-10, AK155, by Transformation of T Lymphocytes with Herpesvirus Saimiri J. Virol., April 15, 2000; 74(8): 3881 - 3887. [Abstract] [Full Text]
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S. Kusaka, A. P. Grailer, J. H. Fechner Jr., E. Jankowska-Gan, T. Oberley, H. W. Sollinger, and W. J. Burlingham Clonotype Analysis of Human Alloreactive T Cells: A Novel Approach to Studying Peripheral Tolerance in a Transplant Recipient J. Immunol., February 15, 2000; 164(4): 2240 - 2247. [Abstract] [Full Text] [PDF]
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 R. A. Terkeltaub IL-10: An "Immunologic Scalpel" for Atherosclerosis? Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2823 - 2825. [Full Text] [PDF]
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S. Sharma, M. Stolina, Y. Lin, B. Gardner, P. W. Miller, M. Kronenberg, and S. M. Dubinett T Cell-Derived IL-10 Promotes Lung Cancer Growth by Suppressing Both T Cell and APC Function J. Immunol., November 1, 1999; 163(9): 5020 - 5028. [Abstract] [Full Text] [PDF]
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M. Rouleau, F. Cottrez, M. Bigler, S. Antonenko, J. M. Carballido, A. Zlotnik, M.-G. Roncarolo, and H. Groux IL-10 Transgenic Mice Present a Defect in T Cell Development Reminiscent to SCID Patients J. Immunol., August 1, 1999; 163(3): 1420 - 1427. [Abstract] [Full Text] [PDF]
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P. Moreau, F. Adrian-Cabestre, C. Menier, V. Guiard, L. Gourand, J. Dausset, E. D. Carosella, and P. Paul IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes Int. Immunol., May 1, 1999; 11(5): 803 - 811. [Abstract] [Full Text] [PDF]
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A. Mathew, I. Kurane, S. Green, D. W. Vaughn, S. Kalayanarooj, S. Suntayakorn, F. A. Ennis, and A. L. Rothman Impaired T Cell Proliferation in Acute Dengue Infection J. Immunol., May 1, 1999; 162(9): 5609 - 5615. [Abstract] [Full Text] [PDF]
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H. Groux, F. Cottrez, M. Rouleau, S. Mauze, S. Antonenko, S. Hurst, T. McNeil, M. Bigler, M.-G. Roncarolo, and R. L. Coffman A Transgenic Model to Analyze the Immunoregulatory Role of IL-10 Secreted by Antigen-Presenting Cells J. Immunol., February 1, 1999; 162(3): 1723 - 1729. [Abstract] [Full Text] [PDF]
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R. Ciubotariu, A. I. Colovai, G. Pennesi, Z. Liu, D. Smith, P. Berlocco, R. Cortesini, and N. Suciu-Foca Specific Suppression of Human CD4+ Th Cell Responses to Pig MHC Antigens by CD8+CD28- Regulatory T Cells J. Immunol., November 15, 1998; 161(10): 5193 - 5202. [Abstract] [Full Text] [PDF]
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B. Balasa, J. D. Davies, J. Lee, A. Good, B. T. Yeung, and N. Sarvetnick IL-10 Impacts Autoimmune Diabetes Via a CD8+ T Cell Pathway Circumventing the Requirement for CD4+ T and B Lymphocytes J. Immunol., October 15, 1998; 161(8): 4420 - 4427. [Abstract] [Full Text] [PDF]
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 R. M. Steinman and M. C. Nussenzweig Inaugural Article: Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance PNAS, January 8, 2002; 99(1): 351 - 358. [Abstract] [Full Text] [PDF]
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) or presence (
) of IL-2.
Purified CD8+ T cells were also stimulated with
cross-linked anti-CD3 mAbs (100 ng/ml) in the absence (
) or
presence (
) of IL-2. As indicated, rIL-10 was added in the cell
culture at different concentrations. B, Purified
CD8+ T cells were stimulated with different doses of
immobilized anti-CD3 mAb either alone (
), with autologous purified monocytes (1 x
106 cell/ml; 
). C, Purified CD8+ T cells and
purified allogeneic monocytes were incubated overnight in the presence
or absence of IL-10 (100 U/ml), washed, and cocultured. White bars,
CD8+ T cells alone; black bars, IL-10-treated
CD8+ T cell alone; white stripped bars, CD8+ T
cells and allogeneic monocytes; black stripped bars, IL-10-treated
CD8+ T cells and allogeneic monocytes; white dotted bars,
CD8+ T cells and IL-10-treated allogeneic monocytes; black
dotted bars, IL-10-treated CD8+ T cells and IL-10-treated
allogeneic monocytes. D, Purified CD8+ T cells
were cultured in the lower compartment of a transwell system in the
presence of immobilized anti-CD3 mAb (20 ng/ml). The
CD8+ T cells were also cocultured with autologous monocytes
either on close contact (white and black stripped bars) or contained in
the upper transwell compartment (white and black dotted bars). IL-10
was added at 100 U/ml (black, black stripped, and black dotted bars).
Cell proliferation was measured by a pulse of [3H]TdR
during the last 12 h of a 5-day incubation for stimulation with
allogeneic monocytes or a 3-day incubation for stimulation with
anti-CD3 mAbs.
or 20 U/ml
(