Transforming Growth Factor β and Immunosuppression in Experimental Visceral Leishmaniasis

ABSTRACT Hamsters infected with Leishmania donovani develop a disease similar to human kala-azar. They present hypergammaglobulinemia, and their T cells do not respond to parasite antigens. This unresponsiveness has been primarily ascribed to defects in antigen-presenting cells (APCs), because these cells are unable to stimulate proliferation of parasite-specific T cells from immunized animals. In this study, we show that APCs (adherent spleen cells) fromL. donovani-infected hamsters produce high levels of the inhibitory cytokine transforming growth factor β (TGF-β). Immunohistochemical studies with an anti-TGF-β monoclonal antibody (MAb) showed that this cytokine is abundantly produced in vivo by the spleen cells of infected animals. In addition, high levels of TGF-β are produced in vitro by infected hamster cells, either spontaneously or after stimulation with parasite antigen or lipopolysaccharide. Furthermore, in vivo-infected adherent cells obtained from spleens ofL. donovani-infected hamsters caused profound inhibition of the in vitro antigen-induced proliferative response of lymph node cells from hamsters immunized with leishmanial antigens. Moreover, this inhibition was totally abrogated by the anti-TGF-β MAb. These results suggest that the immunosuppression observed in visceral leishmaniasis is, at least in part, due to the abundant production of TGF-β during the course of the infection.

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Vaccination Route That Induces Transforming Growth Factor β Production Fails To Elicit Protective Immunity against Leishmania donovani Infection

Infection and Immunity ◽

10.1128/iai.01739-07 ◽

2009 ◽

Vol 77 (4) ◽

pp. 1514-1523 ◽

Cited By ~ 31

Author(s):

Sudipta Bhowmick ◽

Tuhina Mazumdar ◽

Nahid Ali

Keyword(s):

Growth Factor ◽

Leishmania Donovani ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Challenge Infection ◽

Delayed Type Hypersensitivity ◽

Interleukin 12 ◽

No Production

ABSTRACT BALB/c mice immunized intraperitoneally (i.p.) and intravenously (i.v.) with Leishmania donovani promastigote membrane antigens (LAg), either free or encapsulated in liposomes, were protected against challenge infection with L. donovani, whereas mice immunized by the subcutaneous (s.c.) and intramuscular routes were not protected. Protected mice showed strong parasite resistance in both the liver and spleen, along with enhanced immunoglobulin G2a and delayed-type hypersensitivity responses. Again, mice vaccinated through the i.p. and i.v. routes showed high levels of NO production after challenge infection. s.c. vaccination resulted in an increased capacity of the spleen cells to produce prechallenge transforming growth factor β (TGF-β) levels during the in vitro antigen recall response, whereas i.p. immunization induced production of prechallenge gamma interferon, interleukin-12 (IL-12), and IL-4 levels, with a Th1 bias. Exposure to antigen-stimulated splenocyte supernatants of i.p. but not s.c. immunized mice activated macrophages for in vitro parasite killing. As an enhanced level of TGF-β was detected in supernatants from unprotected s.c. immunized mice, neutralization by anti-TGF-β antibody enhanced in vitro macrophage killing activity. The suppressive role of this cytokine was evaluated in vivo by vaccination with liposomal LAg and anti-TGF-β antibody. Upon parasite challenge, these animals showed significant protection in both the liver and spleen. Moreover, the addition of recombinant TGF-β in splenocyte supernatants of i.p. immunized mice in vitro as well as in vivo inhibited the protective ability of the macrophages by the i.p. route. Thus, the induction of high prechallenge TGF-β limits the efficacy of vaccination by routes that are nonprotective.

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Targeting Transforming Growth Factor-β in Metastasis: In Vitro and In Vivo Mechanisms

Transforming Growth Factor-β in Cancer Therapy, Volume II ◽

10.1007/978-1-59745-293-9_37 ◽

2008 ◽

pp. 609-634 ◽

Cited By ~ 1

Author(s):

Michael Reiss

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β

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Prostaglandin E2 Reverses the Effects of DNA Methyltransferase Inhibitor and TGFB1 on the Conversion of Naive T Cells to iTregs

Transfusion Medicine and Hemotherapy ◽

10.1159/000502582 ◽

2019 ◽

Vol 47 (3) ◽

pp. 244-253

Author(s):

Mehmet Sahin ◽

Emel Sahin

Keyword(s):

T Cells ◽

Prostaglandin E2 ◽

Dna Methyltransferase ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Naive T Cells ◽

Naïve T Cells ◽

Dna Methyltransferase Inhibitor

Naturally occurring regulatory T cells (nTregs) are produced under thymic (tTregs) or peripherally induced (pTregs) conditions in vivo. On the other hand, Tregs generated from naive T cells in vitro under some circumstances, such as treatment with transforming growth factor-β (TGFB), are called induced Tregs (iTregs). Tregs are especially characterized by FOXP3 expression, which is mainly controlled by DNA methylation. nTregs play important roles in the suppression of immune response and self-tolerance. The prostaglandin E2 (PGE2) pathway was reported to contribute to regulatory functions of tumor-infiltrating nTregs. In this study, we examined whether PGE2 contributes to the formation of iTregs treated with TGFB1 and 5-aza-2′-deoxycytidine (5-aza-dC), which is a DNA methyltransferase inhibitor. We found that the protein and gene expression levels of FOXP3 and IL-10 were increased in 5-aza-dC and TGFB1-treated T cells in vitro. However, the addition of PGE2 to these cells reversed these increments significantly. In CFSE-based cell suppression assays, we demonstrated that PGE2 decreased the suppressive functions of 5-aza-dC and TGFB1-treated T cells.

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TRAF6 inhibits Th17 differentiation and TGF-β–mediated suppression of IL-2

Blood ◽

10.1182/blood-2009-09-242768 ◽

2010 ◽

Vol 115 (23) ◽

pp. 4750-4757 ◽

Cited By ~ 48

Author(s):

Pedro J. Cejas ◽

Matthew C. Walsh ◽

Erika L. Pearce ◽

Daehee Han ◽

Gretchen M. Harms ◽

...

Keyword(s):

T Cells ◽

Transforming Growth Factor ◽

Interleukin 2 ◽

Transforming Growth Factor Β ◽

Main Function ◽

Normal Numbers ◽

T Helper 17 ◽

Th17 Differentiation

Abstract Transforming growth factor-β (TGF-β) has an essential role in the generation of inducible regulatory T (iTreg) and T helper 17 (Th17) cells. However, little is known about the TGF-β–triggered pathways that drive the early differentiation of these cell populations. Here, we report that CD4+ T cells lacking the molecular adaptor tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) exhibit a specific increase in Th17 differentiation in vivo and in vitro. We show that TRAF6 deficiency renders T cells more sensitive to TGF-β–induced Smad2/3 activation and proliferation arrest. Consistent with this, in TRAF6-deficient T cells, TGF-β more effectively down-regulates interleukin-2 (IL-2), a known inhibitor of Th17 differentiation. Remarkably, TRAF6-deficient cells generate normal numbers of Foxp3-expressing cells in iTreg differentiation conditions where exogenous IL-2 is supplied. These findings show an unexpected role for the adaptor molecule TRAF6 in Smad-mediated TGF-β signaling and Th17 differentiation. Importantly, the data also suggest that a main function of TGF-β in early Th17 differentiation may be the inhibition of autocrine and paracrine IL-2–mediated suppression of Th17 cell generation.

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Estrogen Protects Lenses against Cataract Induced by Transforming Growth Factor-β (TGFβ)

Journal of Experimental Medicine ◽

10.1084/jem.185.2.273 ◽

1997 ◽

Vol 185 (2) ◽

pp. 273-280 ◽

Cited By ~ 71

Author(s):

Angela M. Hales ◽

Coral G. Chamberlain ◽

Christopher R. Murphy ◽

John W. McAvoy

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Hormone Replacement ◽

Transforming Growth Factor Β ◽

Epidemiological Studies ◽

Female Rats ◽

World Population ◽

Damaging Effects

Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-β (TGFβ) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFβ-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFβ and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFβ. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases.

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Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells

Journal of Experimental Medicine ◽

10.1084/jem.20090596 ◽

2009 ◽

Vol 206 (12) ◽

pp. 2701-2715 ◽

Cited By ~ 153

Author(s):

Sven Klunker ◽

Mark M.W. Chong ◽

Pierre-Yves Mantel ◽

Oscar Palomares ◽

Claudio Bassin ◽

...

Keyword(s):

T Cells ◽

Transcription Factors ◽

Cd4 T Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Foxp3 Expression ◽

Human Tonsil ◽

Suppressive Function

Forkhead box P3 (FOXP3)+CD4+CD25+ inducible regulatory T (iT reg) cells play an important role in immune tolerance and homeostasis. In this study, we show that the transforming growth factor-β (TGF-β) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4+ T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-β (CBFβ) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4+ T cells into Foxp3+ iT reg cells was significantly decreased in adoptively transferred CbfbF/F CD4-cre naive T cells into Rag2−/− mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and CbfbF/F CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4+ CD25high CD127− T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-β mRNA compared with CD4+CD25− cells. Furthermore, FOXP3 and RUNX3 were colocalized in human tonsil T reg cells. These data demonstrate Runx transcription factors as a molecular link in TGF-β–induced Foxp3 expression in iT reg cell differentiation and function.

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Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice

Journal of Experimental Medicine ◽

10.1084/jem.20110466 ◽

2011 ◽

Vol 208 (12) ◽

pp. 2489-2496 ◽

Cited By ~ 59

Author(s):

Uri Sela ◽

Peter Olds ◽

Andrew Park ◽

Sarah J. Schlesinger ◽

Ralph M. Steinman

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Spleen Cells ◽

Host Disease ◽

Graft Versus Host ◽

Naturally Occurring

Foxp3+ regulatory T cells (T reg cells) effectively suppress immunity, but it is not determined if antigen-induced T reg cells (iT reg cells) are able to persist under conditions of inflammation and to stably express the transcription factor Foxp3. We used spleen cells to stimulate the mixed leukocyte reaction (MLR) in the presence of transforming growth factor β (TGF-β) and retinoic acid. We found that the CD11chigh dendritic cell fraction was the most potent at inducing high numbers of alloreactive Foxp3+ cells. The induced CD4+CD25+Foxp3+ cells appeared after extensive proliferation. When purified from the MLR, iT reg cells suppressed both primary and secondary MLR in vitro in an antigen-specific manner. After transfer into allogeneic mice, iT reg cells persisted for 6 mo and prevented graft versus host disease (GVHD) caused by co-transferred CD45RBhi T cells. Similar findings were made when iT reg cells were transferred after onset of GVHD. The CNS2 intronic sequence of the Foxp3 gene in the persisting iT reg cells was as demethylated as the corresponding sequence of naturally occurring T reg cells. These results indicate that induced Foxp3+ T reg cells, after proliferating and differentiating into antigen-specific suppressive T cells, can persist for long periods while suppressing a powerful inflammatory disease.

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