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 Hepatocellular Carcinoma Cells Induce Regulatory T Cells and Lead to Poor Prognosis via Production of Transforming Growth Factor-β1

2016 ◽  
Vol 38 (1) ◽  
pp. 306-318 ◽  
Author(s):  
Yi Wang ◽  
Taotao Liu ◽  
Wenqing Tang ◽  
Bin Deng ◽  
Yanjie Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Poor Prognosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vivo Experiments ◽  
Tgf Β1

Background/Aims: Regulatory T cells (Tregs) are associated with a poor prognosis in hepatocellular carcinoma (HCC). The purpose of the study was to explore the mechanisms of Tregs accumulation in HCC. Methods: We analyzed the frequency of Tregs in HCC by flow cytometry and immunohistochemistry. We also established a transforming growth factor (TGF)-β1-knockdown cell line by lentivirus-mediated RNA interference. Mouse CD4+CD25- T cells were cultured in supernatants from various cell lines. Results: HCC patients had a high frequency of Tregs, and high numbers of Tregs correlated with a poor prognosis. Liver cancer cells induced Treg production by secreting TGF-β1. In vivo experiments indicated that knockdown of TGF-β1 reduced the numbers of Tregs and metastatic nodules in mice. Conclusions: These results indicate that cancer-secreted TGF-β1 may increase Tregs, and TGF-β1 knockdown might impair immunosuppression in the tumor microenvironment by decrease Tregs.

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 Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Jochen Michael Rudolph ◽  
Karina Guttek ◽  
Gabriele Weitz ◽  
Clara Antonia Meinke ◽  
Stefanie Kliche ◽  
...  
Keyword(s):  
T Cells ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Severe Disease ◽  
Transforming Growth Factor Β1 ◽  
Regulatory Function ◽  
Platelet Factor ◽  
Tgf Β1

ABSTRACT The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knockout mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knockout mice (ADAPfl/fl PF4-Cretg) (PF4, platelet factor 4). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even under stimulation conditions. ADAPfl/fl PF4-Cretg mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and transforming growth factor β1 (TGF-β1). In vitro, platelets from these mice revealed reduced P-selectin expression, lower levels of TGF-β1 release, diminished integrin αIIbβ3 activation, and decreased fibrinogen binding after stimulation with podoplanin, the ligand of C-type lectin-like receptor 2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of phospholipase Cγ2 (PLCγ2) and extracellular signal-regulated kinase 1/2 (ERK1/2). Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-β1 early after T cell transfer reduced EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo.

Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4107-4114 ◽  
Author(s):  
Lorenzo Cosmi ◽  
Francesco Liotta ◽  
Elena Lazzeri ◽  
Michela Francalanci ◽  
Roberta Angeli ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Functional Features ◽  
Tgf Β1 ◽  
Necrosis Factor

Abstract CD8+CD25+ cells, which expressed high levels of Foxp3, glucocorticoid-induced tumor necrosis factor receptor (GITR), CCR8, tumor necrosis factor receptor 2 (TNFR2), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) mRNAs, were identified in the fibrous septa and medullary areas of human thymus. Activated CD8+CD25+ thymocytes did not produce cytokines, but most of them expressed surface CTLA-4 and transforming growth factor β1 (TGF-β1). Like CD4+CD25+, CD8+CD25+ thymocytes suppressed the proliferation of autologous CD25-T cells via a contact-dependent mechanism. The suppressive activity of CD8+CD25+ thymocytes was abrogated by a mixture of anti-CTLA-4 and anti-TGF-β1 antibodies and it was mediated by their ability to inhibit the expression of the interleukin 2 receptor α chain on target T cells. These results demonstrate the existence of a subset of human CD8+CD25+ thymocytes sharing phenotype, functional features, and mechanism of action with CD4+CD25+ T regulatory cells. (Blood. 2003;102:4107-4114)

scholarly journals CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4034-4044 ◽  
Author(s):  
Carol H. Miao ◽  
Benjamin R. Harmeling ◽  
Steven F. Ziegler ◽  
Benjamin C. Yen ◽  
Troy Torgerson ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Factor Viii ◽  
Cytotoxic T Lymphocyte ◽  
High Titer ◽  
Tumor Necrosis Factor Receptor ◽  
Fviii Activity ◽  
Infectious Tolerance

Abstract Gene transfer of a factor VIII (FVIII) plasmid into hemophilia A (HemA) mice achieved supraphysiologic FVIII expression, but triggered production of high-titer FVIII-specific antibodies and loss of functional FVIII activity. To test whether FVIII-specific regulatory T cells (Tregs) can modulate immune responses against FVIII, we developed a HemA mouse model in which all T cells overexpressed Foxp3 (HemA/Foxp3-Tg). FVIII plasmid therapy did not induce antibody production in HemA/Foxp3-Tg mice. CD4+Foxp3+ T cells isolated from plasmid-treated HemA/Foxp3-Tg mice significantly suppressed proliferation of FVIII-stimulated CD4+ effector T cells. The percentage of CD4+ T cells expressing CD25, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4 increased significantly in spleen and peripheral blood for 9 weeks. Mice receiving adoptively transferred Tregs from FVIII-exposed HemA/Foxp3-Tg mice produced significantly reduced antibody titers compared with controls after initial challenge with FVIII plasmid and second challenge 16 weeks after first plasmid treatment. Adoptively transferred Tregs engrafted and distributed at 2% to 4% in the Treg compartment of blood, lymph nodes, and spleens of the recipient mice and induced activation of endogenous Tregs; the engraftment decreased to negligible levels over 8 to 12 weeks. Antigen-specific Tregs can provide long-lasting protection against immune responses in vivo and limit recall responses induced by a second challenge via infectious tolerance.

Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells

Science ◽  
2018 ◽  
Vol 362 (6417) ◽  
pp. 952-956 ◽  
Author(s):  
Stéphanie Liénart ◽  
Romain Merceron ◽  
Christophe Vanderaa ◽  
Fanny Lambert ◽  
Didier Colau ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Structural Basis ◽  
Amino Terminus ◽  
Latent Form ◽  
Close Proximity ◽  
Tgf Β1

Transforming growth factor–β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (glycoprotein A repetitions predominant) to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-β1 bound to an antibody that stabilizes the complex and blocks release of active TGF-β1. This finding reveals how GARP exploits an unusual medley of interactions, including fold complementation by the amino terminus of TGF-β1, to chaperone and orient the cytokine for binding and activation by αVβ8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by Tregs.

scholarly journals Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

2015 ◽  
Vol 290 (33) ◽  
pp. 20105-20116 ◽  
Author(s):  
Caroline Huygens ◽  
Stéphanie Liénart ◽  
Olivier Dedobbeleer ◽  
Julie Stockis ◽  
Emilie Gauthy ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Transmembrane Protein ◽  
Transforming Growth Factor Β1 ◽  
Tgf Β1

scholarly journals CD4+ CD25+ Regulatory T Cells Modulate the T-Cell and Antibody Responses in Helicobacter-Infected BALB/c Mice

2006 ◽  
Vol 74 (6) ◽  
pp. 3519-3529 ◽  
Author(s):  
Maria Kaparakis ◽  
Karen L. Laurie ◽  
Odilia Wijburg ◽  
John Pedersen ◽  
Martin Pearse ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Bacterial Colonization ◽  
Antibody Responses ◽  
T Helper 1 ◽  
Time Of Infection ◽  
Lymph Node Cells ◽  
Antibody Levels ◽  
And Control

ABSTRACT Gastric Helicobacter spp. induce chronic gastritis that may lead to ulceration and dysplasia. The host elicits a T helper 1 (Th1) response that is fundamental to the pathogenesis of these bacteria. We analyzed immune responses in Helicobacter-infected, normal mice depleted of CD4+ CD25+ T cells to investigate the in vivo role of regulatory T cells (Tregs) in the modulation of Helicobacter immunopathology. BALB/c and transgenic mice were depleted of CD4+ CD25+ T cells by administration of an anti-CD25 antibody either at the time of infection with Helicobacter or during chronic infection and gastritis. Depletion of CD25+ Tregs prior to and during infection of mice with Helicobacter spp. did not affect either bacterial colonization or severity of gastritis. Depletion of CD25+ Tregs was associated with increased Helicobacter-specific antibody levels and an altered isotype distribution. Paragastric lymph node cells from CD25+ Treg-depleted and control infected mice showed similar proliferation to Helicobacter antigens, but only cells from anti-CD25-treated animals secreted Th2 cytokines. CD25+ Tregs do not control the level of gastritis induced by gastric Helicobacter spp. in normal, thymus-intact BALB/c mice. However, CD25+ Tregs influence the cytokine and antibody responses induced by infection. Autoimmune gastritis is not induced in Helicobacter-infected mice depleted of CD25+ Tregs but is induced in CD25+ Treg-depleted mice, which have a higher frequency of autoreactive T cells.

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

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