scholarly journals Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo

2015 ◽  
Vol 7 (284) ◽  
pp. 284ra56-284ra56 ◽  
Author(s):  
Julia Cuende ◽  
Stéphanie Liénart ◽  
Olivier Dedobbeleer ◽  
Bas van der Woning ◽  
Gitte De Boeck ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Activation Mechanism ◽  
Immunosuppressive Activity ◽  
Tumor Vaccines ◽  
Tgf Β1

Regulatory T cells (Tregs) are essential to prevent autoimmunity, but excessive Tregfunction contributes to cancer progression by inhibiting antitumor immune responses. Tregsexert contact-dependent inhibition of immune cells through the production of active transforming growth factor–β1 (TGF-β1). On the Tregcell surface, TGF-β1 is in an inactive form bound to membrane protein GARP and then activated by an unknown mechanism. We demonstrate that GARP is involved in this activation mechanism. Two anti-GARP monoclonal antibodies were generated that block the production of active TGF-β1 by human Tregs. These antibodies recognize a conformational epitope that requires amino acids GARP137–139within GARP/TGF-β1 complexes. A variety of antibodies recognizing other GARP epitopes did not block active TGF-β1 production by Tregs. In a model of xenogeneic graft-versus-host disease in NSG mice, the blocking antibodies inhibited the immunosuppressive activity of human Tregs. These antibodies may serve as therapeutic tools to boost immune responses to infection or cancer via a mechanism of action distinct from that of currently available immunomodulatory antibodies. Used alone or in combination with tumor vaccines or antibodies targeting the CTLA4 or PD1/PD-L1 pathways, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy.

scholarly journals The Suppression of Th1 Response by Inducing TGF-β1 From Regulatory T Cells in Bovine Mycoplasmosis

2020 ◽  
Vol 7 ◽  
Author(s):  
Yamato Sajiki ◽  
Satoru Konnai ◽  
Shinya Goto ◽  
Tomohiro Okagawa ◽  
Kosuke Ohira ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Infected Cattle ◽  
Chronic Infections ◽  
Tgf Β1

Regulatory T cells (Tregs) regulate immune responses and maintain host immune homeostasis. Tregs contribute to the disease progression of several chronic infections by oversuppressing immune responses via the secretion of immunosuppressive cytokines, such as transforming growth factor (TGF)-β and interleukin-10. In the present study, we examined the association of Tregs with Mycoplasma bovis infection, in which immunosuppression is frequently observed. Compared with uninfected cattle, the percentage of Tregs, CD4+CD25highFoxp3+ T cells, was increased in M. bovis-infected cattle. Additionally, the plasma of M. bovis-infected cattle contained the high concentrations of TGF-β1, and M. bovis infection induced TGF-β1 production from bovine immune cells in in vitro cultures. Finally, we analyzed the immunosuppressive effects of TGF-β1 on bovine immune cells. Treatment with TGF-β1 significantly decreased the expression of CD69, an activation marker, in T cells, and Th1 cytokine production in vitro. These results suggest that the increase in Tregs and TGF-β1 secretion could be one of the immunosuppressive mechanisms and that lead to increased susceptibility to other infections in terms of exacerbation of disease during M. bovis infection.

CD28 disruption exacerbates inflammation in Tgf-β1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-β1

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4594-4601 ◽  
Author(s):  
Mizuko Mamura ◽  
WoonKyu Lee ◽  
Timothy J. Sullivan ◽  
Angelina Felici ◽  
Anastasia L. Sowers ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Necrosis Factor Receptor ◽  
Transforming Growth Factor Β1 ◽  
Autoimmune Inflammatory Disease ◽  
Lymph Node Cells ◽  
Tgf Β1

Abstract Tgf-β1-/- mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-β1-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-β1-/- mice, and we link this increase in severity to a reduction in the number of CD4+CD25+ regulatory T cells. CD4+CD25+ T cells develop normally in Tgf-β1-/- mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), αEβ7 integrin, and Foxp3. Adoptive transfer of Tgf-β1-/- splenocytes to Tgf-β1+/+/Rag2-/- mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-β1-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-β1-/- CD4+CD25+ T cells from donor splenocytes. Cotransfer of Tgf- β1-/- CD4+CD25+ T cells clearly attenuated disease in Rag2-/- recipients of CD25+-depleted Tgf-β1-/- spleen and lymph node cells, but suppression was incomplete when compared with Tgf-β1+/+ CD4+CD25+ T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-β1 (TGF-β1) expression and that autocrine TGF-β1 expression is not essential for these cells to suppress inflammation in vivo. (Blood. 2004;103:4594-4601)

scholarly journals Transforming Growth Factor-β Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses

Immunity ◽  
2017 ◽  
Vol 46 (4) ◽  
pp. 660-674 ◽  
Author(s):  
Joanne E. Konkel ◽  
Dunfang Zhang ◽  
Peter Zanvit ◽  
Cheryl Chia ◽  
Tamsin Zangarle-Murray ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
T Helper ◽  
T Helper 17 ◽  
T Helper 17 Cells ◽  
Tissue Specific

Leflunomide induces immunosuppression in collagen-induced arthritis rats by upregulating CD4+CD25+ regulatory T cells

2010 ◽  
Vol 88 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Ting-Yu Wang ◽  
Jun Li ◽  
Chang-Yu Li ◽  
Yong Jin ◽  
Xiong-Wen Lü ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Con A ◽  
Collagen Induced Arthritis ◽  
Foxp3 Mrna ◽  
Tgf Β1

This study was to investigate the effect of leflunomide on the immunosuppressive CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) in collagen-induced arthritis (CIA) rats. CIA was induced by collagen type II in Wistar rats. Immunofluorescence flow cytometry and RT-PCR were used to determine the proportion of CD4+CD25+ Tregs and the expression of Foxp3 mRNA, respectively. Proliferation of T lymphocytes was assayed with MTT reagent, and the level of transforming growth factor β1 (TGF-β1) in the supernatant of concanavalin A (Con A)-induced T lymphocytes was determined by ELISA kit. Our investigations demonstrated that inhibition of arthritis by leflunomide was related to changes in CD4+CD25+ Tregs. In addition, A771726, which is the active metabolite of leflunomide, promoted the differentiation of spleen lymphocytes into CD4+CD25+ Tregs, increased antiinflammatory cytokine TGF-β1 secretion, and adjusted the activity of Con A-induced lymphocytes in vitro.

scholarly journals Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor–β1

2006 ◽  
Vol 203 (4) ◽  
pp. 1021-1031 ◽  
Author(s):  
Ichiko Kinjyo ◽  
Hiromasa Inoue ◽  
Shinjiro Hamano ◽  
Satoru Fukuyama ◽  
Takeru Yoshimura ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Immune Responses ◽  
Leishmania Major ◽  
Transforming Growth Factor ◽  
Dominant Negative ◽  
Conditional Knockout ◽  
Cytokine Signaling ◽  
T Helper ◽  
Tgf Β1

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell–specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4+ T cells produced more transforming growth factor (TGF)-β1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-β1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-β1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-β1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-β1 and IL-10 through modulating STAT3 activation.

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Blood ◽  
2013 ◽  
Vol 121 (7) ◽  
pp. 1102-1111 ◽  
Author(s):  
Roudaina Nasser ◽  
Mireia Pelegrin ◽  
Marc Plays ◽  
Laurent Gros ◽  
Marc Piechaczyk
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Regulatory T Cells ◽  
Immunosuppressive Activity ◽  
Key Points

Key Points Mab-based immunotherapy prevents Treg expansion and limits immunosuppressive activity.

scholarly journals CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

2002 ◽  
Vol 196 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Ciriaco A. Piccirillo ◽  
John J. Letterio ◽  
Angela M. Thornton ◽  
Rebecca S. McHugh ◽  
Mizuko Mamura ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Transforming Growth Factor ◽  
Cell Contact ◽  
Suppressor Function ◽  
Tgf Β1

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25−T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact–dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti–TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3−/− or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1–induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1−/− mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1.

The Link Between Seminal Cytokine Interleukin 18, Female Circulating Regulatory T Cells, and IVF/ICSI Success

2018 ◽  
Vol 26 (8) ◽  
pp. 1034-1044 ◽  
Author(s):  
Marina Nikolaeva ◽  
Alina Babayan ◽  
Elena Stepanova ◽  
Alla Arefieva ◽  
Tatiana Dontsova ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Transforming Growth Factor ◽  
Embryo Implantation ◽  
Female Reproductive Tract ◽  
Vitro Fertilization ◽  
Treg Frequency ◽  
Tgf Β1

Seminal plasma (SP) is thought to be a crucial factor which affects the expansion of regulatory T cells (Tregs) in female reproductive tract during embryo implantation. We propose that seminal transforming growth factor (TGF) β1 is responsible for local accumulation of circulating Tregs, which manifests as changes in Treg frequency in peripheral blood, whereas seminal interleukin (IL) 18 interferes with TGF-β1-dependent cellular reactions. The purpose of the present study is to determine whether the frequency of circulating Tregs is associated with the levels of seminal cytokines and pregnancy establishment in women exposed to partner’s SP during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle. Twenty-nine women were exposed to SP via timed intercourse before the day of ovum pickup (day-OPU) and also subjected to intravaginal SP application just after OPU. Measurements of seminal TGF-β1 and IL-18 were made by FlowCytomix technology. The percentage of CD4+CD25+CD127low+/ – Tregs among total circulating CD4+ T cells was determined by flow cytometry and the difference between Treg values on the day of embryo transfer and day-OPU was calculated. The percentage of Tregs on the day-OPU, identified as a predictive factor of clinical pregnancy after IVF/ICSI, showed a positive correlation with IL-18 concentration and content of this cytokine per ejaculate ( P < .001 and P < .004, respectively) and negative correlation with the TGF-β1/IL-18 ratio ( P < .014).These findings indicate that the adverse effect of seminal IL-18 excess on implantation may be realized by the prevention of postcoital TGF-β1-related migration of circulating Tregs, which clearly manifests as elevated level of Treg frequency in peripheral blood.

scholarly journals Transforming Growth Factor (TGF)-β1–producing Regulatory T Cells Induce Smad-mediated Interleukin 10 Secretion That Facilitates Coordinated Immunoregulatory Activity and Amelioration of TGF-β1–mediated Fibrosis

2003 ◽  
Vol 198 (8) ◽  
pp. 1179-1188 ◽  
Author(s):  
Atsushi Kitani ◽  
Ivan Fuss ◽  
Kazuhiko Nakamura ◽  
Fumiyuki Kumaki ◽  
Takashi Usui ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
T Cell Response ◽  
Luciferase Reporter ◽  
Trinitrobenzene Sulfonic Acid ◽  
Luciferase Reporter Construct ◽  
Tgf Β1

Interleukin (IL)-10 and transforming growth factor (TGF)-β1 are suppressor cytokines that frequently occur together during a regulatory T cell response. Here we used a one gene doxycycline (Dox)-inducible plasmid encoding TGF-β1 to analyze this association and test its utility. In initial studies, we showed that intranasal administration of this plasmid (along with Dox) led to the appearance of TGF-β1–producing cells (in spleen and lamina propria) and the almost concomitant appearance of IL-10–producing cells. Moreover, we showed that these cells exert Dox-regulated suppression of the T helper cell (Th)1-mediated inflammation in trinitrobenzene sulfonic acid colitis. In subsequent in vitro studies using retroviral TGF-β1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-β1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-β1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-β1 plasmid administration ameliorates bleomycin-induced fibrosis in wild-type but not IL-10–deficient mice, strongly suggesting that the amelioration is IL-10 dependent and that IL-10 protects mice from TGF-β1–mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-β1 is not fortuitous, but instead fulfills important requirements of TGF-β1 function after its secretion by regulatory T cells.

Sign in / Sign up

Export Citation Format

Share Document