Everolimus Enhances Immunomodulation of Alloreative T Cells by Multipotent Stromal Cells Due to Transforming Growth Factor - β Dependent Mechanisms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2545-2545 ◽  
Author(s):  
Razvan George Racila ◽  
Wolfgang Melchinger ◽  
Jürgen Finke ◽  
Reinhard E Marks
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Mtor Inhibitors ◽  
Immunosuppressive Drug ◽  
T Cell Suppression ◽  
Ifn Γ ◽  
Cell Suppression ◽  
Suppression Assay

Abstract Abstract 2545 Steroid refractory Graft versus Host Disease (GvHD) is a serious complication following allogeneic haematopoietic stem cell transplantation (HCT). Recently, novel therapeutic strategies involving multipotent stromal cell (MSC) transfusions have shown promising clinical results. Nevertheless, little is known on the interaction between MSC and immunosuppressive agents currently used for GvHD treatment and prophylaxis. Here we investigated the effects of mammalian target of rapamycin (mTOR) and calcineurin inhibitors on MSC mediated allogeneic T cell suppression. Since both of these drugs inhibit protein translation and exert potent antiproliferative effects, we assumed that MSC immunomodulation would be abrogated following mTOR or calcineurin inhibitor treatment. In an experimental in vitro suppression assay human MSC were pre-incubated with either everolimus or cyclosporine at concentrations currently used in the clinical practice. After 3 hours, MSC were washed several times to remove any immunosuppressive drug in the supernatant and cultured with magnetically sorted allogeneic human CD4+ or CD8+ T cells at a ratio of 1 MSC to 10 T cells prior to T cell activation with anti-CD3/CD28 coated beads. Surprisingly, MSC treated with mTOR inhibitors exerted significantly enhanced suppression of allogeneic CD4+ T cell proliferation (76%+/−12%) as determined by thymidine incorporation in comparison to MSC pre-incubated with cyclosporine (59%+/−12%) or untreated MSC (39%+/−10%). Similar results were obtained when MSC were cultured with CD8+ T cells. High pressure liquid chromatography (HPLC) did confirm that no remaining immunosuppressive drug in the culture supernatant was responsible for this observation. Subsequently we investigated, whether regulatory T cells (Treg) expansion would account for this enhanced MSC mediated immunosuppression. When everolimus treated MSC were added to CD4+ T cells in the suppression assay, significantly more lymphocytes expressed a regulatory CD4+CD25high FOXP3high phenotype (22%) in short and long term cultures while cyclosporine pre-treatment of MSC induced a Treg population (10%) comparable to untreated MSC (7,3%). When neutralizing antibodies against transforming growth factor-beta (TGF-β) were added, lower numbers of Tregs were induced by mTOR treated MSC (15,7%), cyclosporine treated MSC (8,8%) and untreated MSC (7,3%). In addition, several reports proposed indoleamine 2,3-dioxygenase (IDO) as a potent mediator of MSC dependent immunosuppression, since IDO expression results in depletion of tryptophan that is essential for cell proliferation. In the presence of interferon-gamma (IFN-γ), MSC up-regulate IDO and exert enhanced suppression of alloreactive T cell proliferation. However, when MSC pre-treated with everolimus were stimulated with IFN-γ, IDO expression was reduced. In addition IFN-γ signalling abrogated Treg expansion induced by everolimus pre-treated MSC. Thus, combined effects of mTOR inhibitors and IFN-γ signalling reduced MSC mediated T cell suppression. Collectively, these data suggest that MSC pre-treated with mTOR inhibitors induce enhanced immunosuppressive capacity towards allogeneic T cells due to induction and expansion of Tregs in a, at least partially, TGF-β dependent way. In contrast, mTOR inhibitors and IFN-γ enhance MSC immunomodulation by independent mechanisms. However, when combined they antagonize each others effects. In conclusion, our results support the combined use of mTOR inhibitors and MSC for the treatment of steroid refractory GvHD. This combination may induce Treg expansion that can treat GvHD without limiting graft versus tumor effects. Additionally, determination of IFN-γ serum levels may predict the outcome of this combined therapy. Disclosures: No relevant conflicts of interest to declare.

Reciprocal Interaction Between Osteoclasts and T Cells: Osteoclasts Inhibit T Cell Proliferation by IDO Produced in Response to T Cell-Derived IFN-γ and CD40 Ligand

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 694-694
Author(s):  
Haiyan Li ◽  
Yong Lu ◽  
Sungyoul Hong ◽  
Jianfei Qian ◽  
Zhiqiang Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd40 Ligand ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
T Cell Suppression ◽  
Activated T Cell ◽  
Ifn Γ ◽  
Cell Suppression

Abstract Abstract 694 Osteoclasts (OCs), the responsible cells for bone resorption, are derived from monocytic precursor cells, with the stimulation of macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor κb ligand (RANKL). The formation and activity of OCs can be either promoted by activated T cell derived RANKL, IL-17, or suppressed by T cell derived IFN-γ, IL-10, and IL-4. On the other hand, OCs express MHC, and costimulatory molecules, secrete IL-10, TGF-β, TNF-α and IL-6 and can act as antigen presenting cells to activate T cells, which indicates that OCs can be considered as immune cells. However, the immune function of OCs is largely unknown, and whether activated T cells can regulate the immune function of OCs is also unclear. In this study, we investigated the effect of OCs on T cell responses, and the cross regulation between activated T cells and immune regulatory OCs. Results showed that autologous OCs could inhibit the proliferation of CD4+ T cells activated by allogeneic antigen, tetanus toxin, staphylococcal enterotoxin B, and anti-CD3/CD28 antibodies. The inhibitory rate range varied from 63% to 88%. To identify the mechanism of OC-mediated T cell suppression, we blocked or inhibited TGF-β, IL-10, (prostaglandin E2) PGE-2, and indoleamine 2,3-dioxygenase (IDO) with neutralizing antibodies or specific inhibitors during the coculture. Results showed that only 1-methyl-DL-tryptophan (1-MT, an IDO inhibitor) could rescue the T cell proliferation, which suggested that OCs mediated the T cell suppression through IDO. To confirm this result, we knocked down IDO expression in OCs with siRNA and found that T cell proliferation was restored completely. As normal OCs didn't express IDO, next we investigated which molecules induced IDO expression in OCs, when cocultured with activated T cells. Results showed that blocking IFN-γ and CD40 ligand (CD40L) could inhibit IDO expression in OCs and rescue the T cell proliferation, and recombinant IFN-γ and soluble CD40L could induce IDO expression in OCs, synergistically. In conclusion, our study identified that OCs can function as immune regulatory cells to suppress T cell proliferation through IDO, which is induced by activated T cell derived IFN-γ and CD40L. This study provides new insight into the reciprocal interaction between OCs and T cells and may be helpful to develop novel therapeutic strategies for diseases involved in both bone and immune systems, such as bone-invasive tumors and autoimmune arthritis. Disclosures: No relevant conflicts of interest to declare.

Pentostatin Is Advantageous Relative to Fludarabine for in Vivo Murine T Cell Depletion, Suppression of T Cell Cytokine Secretion, and Inhibition of HVGR

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3483-3483
Author(s):  
Jacopo Mariotti ◽  
Jason Foley ◽  
Kaitlyn Ryan ◽  
Nicole Buxhoeveden ◽  
Daniel Fowler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytokine Secretion ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
T Cell Suppression ◽  
Ifn Γ ◽  
Cell Suppression

Abstract Although fludarabine and pentostatin are variably utilized for conditioning prior to clinical allogeneic transplantation, limited data exists with respect to their relative efficacy in terms of host immune T cell depletion and T cell suppression. To directly compare these agents in vivo in a murine model, we compared a regimen of fludarabine plus cyclophosphamide (FC) similar to one that we previously developed (Petrus et al, BBMT, 2000) to a new regimen of pentostatin plus cyclophosphamide (PC). Cohorts of mice (n=5–10) received a three-day regimen consisting of P alone (1 mg/kg/d), F alone (100 mg/kg/d), C alone (50 mg/kg/d), or combination PC or FC. Similar to our previous data, administration of P, F, or C alone yielded minimal host T cell depletion (as measured by enumeration of splenic CD4+ and CD8+ T cells) and minimal T cell suppression (as determined by CD3, CD28 co-stimulation of a constant number of remaining splenic T cells and measuring resultant cytokine secretion by multi-analyte assay). The PC and FC regimens were similar in terms of myeloid suppression (p=.2). However, the PC regimen was more potent in terms of depleting host CD4+ T cells (remaining host CD4 number [× 10^6/spleen], 2.1±0.3 [PC] vs. 4.4±0.6 [FC], p<0.01) and CD8+ T cells (remaining host CD8 number, 1.7±0.2 [PC] vs. 2.4±0.5 [FC], p<0.01). Moreover, the PC regimen yielded greater T cell immune suppression than the FC regimen (cytokine values are pg/ml/0.5×10^6 cells/ml; all comparisons p<0.05) with respect to capacity to secrete IFN-γ (13±5 [PC] vs. 48±12 [FC]), IL-2 (59±44 [PC] vs. 258±32 [FC]), IL-4 (34±10 [PC] vs. 104±12 [FC]), and IL-10 (15±3 [PC] vs. 34±5 [FC]). In light of this differential in both immune T cell depletion and suppression of T cell effector function, we hypothesized that T cells from PC-treated recipients would have reduced capacity to mediate a host-versus-graft rejection response (HVGR) relative to FC-treated recipients. To directly test this hypothesis, we utilized a host T cell add-back model of rejection whereby BALB/c hosts were lethally irradiated (1050 cGy; day -2), reconstituted with host-type T cells from PC- or FC-treated recipients (day -1; 0.1 × 10^6 T cells transferred), and finally challenged with fully MHC-disparate transplantation (B6 donor bone marrow cells, 10 × 10^6 cells; day 0). In vivo HVGR was quantified by the following method at day 7 post-BMT: harvest of splenic T cells, stimulation with host- or donor-type dendritic cells, and use of six-color flow cytometry to detect host T cells, CD4 and CD8 subsets, and cytokine secretion by capture method. Consistent with our hypothesis, PC-treated cells acquired greatly reduced alloreactivity in vivo relative to FC-treated cells: the percentage of host CD4+ T cells secreting IFN-γ in an allospecific manner was 2.3±0.8% in recipients of PC-treated T cells and 62.7±13.4% in recipients of FC-treated cells (p<0.001). Similarly, the percentage of host CD8+ T cells secreting IFN-γ in an allospecific manner was 8.6±2.8% in recipients of PC-treated T cells and 92.7±4.1% in recipients of FC-treated T cells (p<0.001). We therefore conclude that at similar levels of myeloid suppression, the PC regimen is superior to the FC regimen in terms of murine T cell depletion, suppression of global T cell cytokine secretion, and inhibition of in vivo capacity to acquire allospecificity in response to fully genetically disparate marrow allografts. These data provide a rationale to develop PC regimens as an alternative to currently utilized FC regimens.

Mesenchymal Stem Cells (MSCs) Suppress T Cell Proliferation by a Novel NO-stat5 Dependent Mechanism.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1393-1393
Author(s):  
Kazuya Sato ◽  
Katsutoshi Ozaki ◽  
Iekuni Oh ◽  
Keiko Hatanaka ◽  
Tadashi Nagai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
T Cell Proliferation ◽  
Cd8 Cells ◽  
T Cell Suppression ◽  
Cell Suppression ◽  
Dependent Mechanism

Abstract Mesenchymal stem cells (MSCs) are attractive source for regenerative therapy as they have been shown to be capable of differentiating into adipocytes, chondrocytes, osteoblasts, myocytes, cardiomyocytes, and neural precursors. MSCs have also been shown to suppress T cell proliferation in vitro and were reported to be effective as a treatment for acute graft-versus-host disease (GVHD) but the underlying molecular mechanisms for T cell suppression are uncertain. So far, TGF-β, HGF, and PGE2 were shown to be candidates as molecules causing the suppression. To address the molecular mechanisms, we used primary mouse MSCs derived from bone marrow cells and CFSE (carboxyfluorescein diacetate succinimidyl ester) or thymidine uptake for T cell proliferation assay. Co-culture of MSCs inhibited T cell proliferation induced by PMA plus Ionomycin, suggesting that TCR and signaling molecules interacting with TCR such as Lck and ZAP70 are not involved and that downstream signals of PMA plus Ionomycin are essential for the suppression by MSCs. The proliferation of either purified CD4 or CD8 cells induced by PMA plus Ionomycin was also inhibited by co-culture with MSCs, indicating MSCs suppression is active on both CD4 and CD8 cells. Stat5 phosphorylation in activated T cells was suppressed by co-culture with MSCs. Induction of cell-cycle promoting proteins such as CDK6, Cyclin D2, and Cyclin E by mitogenic stimulation were inhibited and suppression of a cell-cycle inhibitor, Kip1, was abolished. A previous report showed that T cells from stat5 deficient mice failed to induce cell-cycle promoting proteins and were not be able to proliferate on the stimulation through TCR. It was also reported that Nitric Oxide (NO) suppressed stat5 phosphorylation. Taken together with these reports, we hypothesized that NO is another candidate for the cause of suppression. In fact, NO synthase inhibitor (N-nitro-L-arginine methyl ester) recovered T cell proliferation from the suppression by MSCs in a dose-dependent manner. The amount of NO production and the strength of T cell suppression were parallel and dependent on the number of MSCs. MSCs blocked production of IFNγ but induction of T cell activation markers such as CD25 and CD69 and production of IL-2 were unaffected as reported. Our data suggest that MSCs block stat5 phosphorylation by production of NO, resulting in that T cells can neither proliferate nor produce high level of IFNγ. Here we demonstrate a new critical NO-stat5 dependent mechanism for T cell suppression by MSCs.

Mesenchymal Stem Cells Produce Nitric Oxide, a Key Molecule for T Cell Suppression, upon Interaction with Activated T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2556-2556
Author(s):  
Kazuya Sato ◽  
Katsutoshi Ozaki ◽  
Iekuni Oh ◽  
Akiko Meguro ◽  
Reine Tatara ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Knockout Mice ◽  
No Synthase ◽  
T Cell Proliferation ◽  
No Production ◽  
Activated T Cells ◽  
T Cell Suppression ◽  
Cell Suppression

Abstract The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. We demonstrated that nitric oxide (NO) is important for T cell suppression by MSCs (ASH 2005, 403a). Here we further demonstrate that the production of NO in the presence of MSCs is dependent on CD4 or CD8 T cells but not on CD19 B cells. MSCs inhibits B cell proliferation induced by LPS, suggesting that mechanisms of supppression by MSCs are different between T cells and B cells. Inducible NO synthase was exclusively detected in MSCs co-cultured with activated T cells, indicating that the producer of NO is MSC. Experiments with transwell system revealed that separation by transwell membrane reduces the induction of NO and T cell suppression. RAW246.7 macrophage cell line showed a similar transwell-mediated inhibition, suggesting that the inhibition by transwell is a common feature of NO and that direct contact is critical for efficient NO production and T cell suppression. Furthermore, inhibitors of prostaglandin synthase or NO synthase restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor-β-neutralizing antibody had no effect. In the view of that NO is upstream of PGE2, NO may be a key regulator of T cell suppression induced by MSCs. Finally, we used inducible NO synthase knockout mice to reconfirm all results here. MSCs from knockout mice did not produce NO even in the presence of activated wild type T cells and had a reduced ability to suppress T cell proliferation. Meanwhile, proliferation of splenocytes from knockout mice was suppressed in the presence of wild type MSCs and NO production was readily detected, confirming that NO produced by MSCs plays a critical role in T cell suppression.

scholarly journals Neutrophils Lose the Capacity to Suppress T Cell Proliferation Upon Migration Towards Inflamed Joints in Juvenile Idiopathic Arthritis

2022 ◽  
Vol 12 ◽  
Author(s):  
Sabine Arve-Butler ◽  
Anki Mossberg ◽  
Tobias Schmidt ◽  
Charlotte Welinder ◽  
Hong Yan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Synovial Fluid ◽  
Suppressive Effect ◽  
T Cell Proliferation ◽  
Cell Contact ◽  
Ros Production ◽  
T Cell Suppression ◽  
Cell Suppression

Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4+ T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in an in vitro transmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4+ T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint.

scholarly journals Amygdalin promotes the activity of T cells to suppress the progression of HBV-related hepatocellular carcinoma via the JAK2/STAT3 signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ruoyu Wang ◽  
Dong Zhang ◽  
Kewei Sun ◽  
Jianping Peng ◽  
Wenfang Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Viability ◽  
Caspase 3 ◽  
Invasion And Migration ◽  
Ifn Γ ◽  
And Migration ◽  
Cellular Immune

Abstract Background Hepatitis B virus (HBV) infection is a high-risk factor of hepatocellular carcinoma (HCC). Cellular immune responses are essential for HCC development, and the CD4+ and CD8+ T subtypes are identified as the primary anti-tumor immune cells. In the study, we investigated the effect and mechanism of amygdalin in the cellular immune response in HBV-related HCC and HCC progression. Methods The cell proliferation was examined by MTT analysis. Cells metastasis ability was detected by Invasion and migration assays. Quantification of apoptotic cells was performed with Flow cytometer assay. The protein levels of p-STAT3, STAT3, p-JAK2, JAK2, caspase-3, cleaved caspase-3 were detected by performing immunoblotting assays. Results We demonstrate that amygdalin treatment could rescue the HBV-T cell viability and IFN-γ and TNF-αproduction. In HBV-T cells, the MFI levels of CD8+ are lower than that in NC-T cells. Moreover, the phosphorylation levels of STAT3 and JAK2 are higher in HBV-T cells, compared to those in NC-T cells, and then reduced by amygdalin treatment. Co-culture with HBV-T cells could reduce IFN-γ and TNF-α, production while increase IL-6 and IL-10 production in HepG2.2.15 cells; these alterations could be partially reversed by amygdalin pretreatment. Finally, co-culture with HBV-T cells significantly promoted the cell viability, inhibited the apoptosis, and promoted the migration of HepG2.2.15 cells, and these alterations could be partially reversed by amygdalin treatment. Conclusion Our findings provide a rationale for further studies on the functions and mechanism of amygdalin inhibiting HBV-related HCC cell proliferation, invasion, and migration via T cell-mediated tumor immunity.

scholarly journals Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

2002 ◽  
Vol 195 (6) ◽  
pp. 695-704 ◽  
Author(s):  
Michel Gilliet ◽  
Yong-Jun Liu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Transforming Growth Factor ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Plasmacytoid Dendritic Cells ◽  
Target Cells ◽  
Ifn Γ

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

scholarly journals The Role of Interleukin-10 (IL-10) in IL-15–Mediated T-Cell Responses

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4513-4521 ◽  
Author(s):  
Dieter Körholz ◽  
Ursula Banning ◽  
Halvard Bönig ◽  
Markus Grewe ◽  
Marion Schneider ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Interleukin 10 ◽  
T Cell Proliferation ◽  
Cell Production ◽  
Cd25 Expression ◽  
Tnf Α ◽  
Ifn Γ

Abstract Interleukin-15 (IL-15) is a potent T-cell stimulating factor, which has recently been used for pre-clinical in vivo immunotherapy. Here, the IL-15 effect on CD3-stimulated peripheral human T cells was investigated. IL-15 induced a significant T-cell proliferation and upregulated CD25 expression. IL-15 significantly enhanced T-cell production of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-10. Between 10- and 100-fold greater concentrations of IL-15 were necessary to reach a biological effect equivalent to that of IL-2. Blockade of IL-2 binding to the high-affinity IL-2 receptor did not affect the IL-15 effects, suggesting that IL-15 did not act by inducing endogenous IL-2. Exogenously administered IL-10 significantly reduced the IL-15 and IL-2–mediated IFN-γ and TNF-α production, whereas T-cell proliferation and CD25 expression were not affected. The inhibitory effects of exogenously administered IL-10 on T-cell cytokine production appeared indirect, and are likely secondary to decreased IL-12 production by accessory cells. Inhibition of endogenous IL-10 binding to the IL-10 receptor significantly increased IFN-γ and TNF-α release from T cells. These data suggest that endogenous IL-10 can regulate activated T-cell production of IFN-γ and TNF-α via a paracrine negative feedback loop. The observations of this study could be of relevance for the therapeutic use of IL-15 in vivo.

Sign in / Sign up

Export Citation Format

Share Document