Transforming growth factor-beta: An important role in CD4<sup>+</sup>CD25<sup>+</sup>regulatory T cells and immune tolerance

Zhang, Lianjun; Yi, Huanfa; Xia, Xue-Pei; Zhao, Yong

doi:10.1080/08916930600753903

Cited by 71 publications

(52 citation statements)

References 72 publications

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“…5,29,30 Foxo3 is implicated in apoptosis induction, and, importantly, deficiency in Foxo3 leads to impaired apoptosis in vitro and in vivo. [13][14][15]31 Consistent with the pro-apoptotic role of Foxo3, in this study, we observed that the silencing of Foxo3 led to an increase in the number of APCs and to a reduction in the percentage of DCs undergoing apoptosis in mice vaccinated with the Figure 7 The effect of IL-6 produced during the HER-2/neu-specific T-cell responses and the therapeutic effect of the hN'-neu-Foxo3 shRNA DNA vaccine. (a) GFP-expressing CD11c + cells were isolated from the inguinal lymph nodes 72 h after the last DNA vaccination.…”

Section: Discussionsupporting

confidence: 62%

“…Second, the induction of specific cytotoxic CD8 + T-cell responses by gene gun-delivered DNA vaccines is likely to be achieved by CD4 + Th1 cell-dependent and CD4 + Th1 cell-independent pathways. Third, the MBT-2 tumor implantation may induce negative regulatory CD4 + T cells, including CD4 + CD25hi T cells, 31 IL-10-producing CD4 + T-regulatory type 1 (Tr1) cells 34 or transforming growth factor-b-producing CD4 + (Th3) regulatory cells, 35 thereby partially suppressing the effects of specific CD8 + CTLs. Previous reports have shown that the depletion of CD4 + T cells dramatically induces the penetration of CD8 + T cells into the tumor sites of a B16 melanoma model.…”

Section: Discussionmentioning

confidence: 99%

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RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

Chang

Yen

et al. 2010

Gene Ther

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The transcription factor Forkhead box O3 (Foxo3) has a critical role in suppressing the expansion of antigen-specific effector T-cell populations; hence, Foxo3 is a potential target for enhancing the antitumor immunity of cancer vaccines. In this report, we evaluated the potential of RNA interference (RNAi)-mediated silencing of Foxo3 in antigen-presenting cells as an adjuvant for HER2/neu DNA cancer vaccines. Bicistronic plasmids expressing the N-terminal extracellular domain of human HER-2/neu and the Foxo3 short hairpin RNA (hN'-neu-Foxo3 shRNA) or the scrambled control (hN'-neu-scramble shRNA) were subcutaneously injected into mice by gene gun administration to elicit antitumor immunity against p185neu-overexpressing MBT-2 bladder tumor cells. We found that mice treated with hN'-neu-Foxo3 shRNA showed greater reductions in tumor growth and longer survival times than mice treated with hN'-neu-scramble shRNA, indicating that the silencing of Foxo3 enhanced the antitumor efficacy of the HER-2/neu cancer vaccine. Cytotoxicity analyses further revealed that the Foxo3 shRNA-enhanced antitumor effect was associated with significant increases in the number of functional CD8 + T cells and in the levels of cytotoxic T lymphocytes activity. Interleukin-6 was induced by hN'-neu-Foxo3 shRNA treatment but did not have a critical role in the antitumor effect of the hN'-neu-Foxo3 shRNA vaccine. Moreover, in vivo lymphocyte depletion analyses confirmed that the antitumor efficacy of the hN'-neu-Foxo3 shRNA vaccine depended on functional CD8 + T cells. Finally, Foxo3 suppression was shown to markedly improve the effect of the HER-2/neu DNA vaccine in limiting the growth and lung metastases of MBT-2 cells. Overall, these results support RNAi-mediated silencing of Foxo3 as an effective strategy to enhance the therapeutic antitumor effect of HER-2/neu DNA vaccines against p185neu-positive tumors.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

Chang

Yen

et al. 2010

Gene Ther

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“…The induction of regulatory T cells by anti-CD3 antibody has also been demonstrated in the animal model for diabetes, in which there was induction of CD4+CD25+ regulatory T cells that differ from the naturally occurring CD4+CD25+ regulatory T cells. The induced immune regulation was dependent on TGF-β, and raise the possibility that the induced T cells exert their regulatory function via TGF-β (3,18,23). We observed an increase of CD4+CD25−LAP+ T cells after oral anti-CD3 in mice (19).…”

Section: Discussionmentioning

confidence: 51%

“…Another mechanism that has been proposed is down regulation of the T cell receptor (TCR) complex after internalization. Finally, it has been shown in the mouse model of autoimmune diabetes that IV anti-CD3 therapy induces CD4+CD25+regulatory T cells that act in a TGF-β dependent fashion (3,18) and we have found the induction of CD4+CD25−LAP+ TGF-β dependent regulatory T cells following oral administration of anti-CD3 (19).…”

Section: Introductionmentioning

confidence: 81%

In vitro induction of regulatory T cells by anti-CD3 antibody in humans

Abraham

Karni

Dembinsky

et al. 2008

Journal of Autoimmunity

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Therapy with anti-CD3 antibody is effective in controlling models of autoimmune diseases and can reverse or prevent rejection of grafts. We studied the in vitro immunomodulatory effect of anti-CD3 treated human T cells. CD4 + T cells were stimulated with plate bound anti-CD3 and cultured for 12 days after which they were cultured with autologous peripheral blood mononuclear cells (PBMCs) and stimulated with soluble anti-CD3. We found that CD4 + T cells that were stimulated with anti-CD3 (T αCD3 ) markedly suppressed the proliferation and cytokine production of autologous PBMCs. These regulatory T cells were not induced by incubation with isotype control (T Control ) antibody or when anti-CD3 was combined with high doses of anti-CD28 (T αCD3/CD28 ). T αCD3 regulatory cells were anergic and produced lower levels of IFN-γ, TNF-α and IL-2, and higher levels of TGF-β than T Control or T αCD3/CD28 .There were no differences in the expression of CD25, CD45RB or CTLA-4 on T αCD3 as compared to T Control or T αCD3/CD28 and CD4 + CD25 − T αCD3 cells were identical to CD4 + CD25 + T αCD3 cells in their in vitro suppressive properties. Recombinant IL-2 in vitro abrogated the suppressive effect of T αCD3 . The suppressive effect was not related to apoptosis, was independent of HLA since T αCD3 also suppressed allogeneic PBMCs, and was not related to soluble factors. Finally, no suppression was observed when non T cells were removed from culture or when cultures were stimulated with plate bound anti-CD3, consistent with the ability of T αCD3 to downregulate CD80 on dendritic cells in co-culture experiments. Thus, we have identified human T cells with strong in vitro regulatory properties induced in vitro by anti-CD3 which appear to act in a non-HLA restricted fashion by affecting antigen presenting cells.

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“…One source of TGF-b is regulatory T cells (Tregs), and while the exact relationship between Tregs and TGF-b is still unclear [22,23], there is a large body of data demonstrating that Tregs exert their regulatory effects at least in part through TGF-b [24][25][26][27][28]. Our recent studies failed to define a role for regulatory T cells in regulating CD8 + T cell function in muscle of T. cruzi-infected mice as determined by depletion (or functional inactivation [29]) of Tregs using PC61 anti-CD25 Ab [30].…”

Section: Discussionmentioning

confidence: 99%

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

et al. 2007

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Infection with the protozoan parasite Trypanosoma cruzi leads to chronic infection, with parasite persistence primarily in muscle tissue. CD8 + T cells isolated from muscle tissue of T. cruzi-infected mice display decreased production of IFN-c in response to T cell receptor engagement. The expression of TGF-b at the site of CD8 + T cell dysfunction and parasite persistence suggested that this immunoregulatory cytokine might play a role in these processes. Mice expressing a T cell-specific dominant negative TGF-b receptor type II (DNRII) were therefore infected with T. cruzi. Infection of DNRII mice resulted in massive CD8 + T cell proliferation, leading to increased numbers but decreased frequencies of antigen-specific CD8 + T cells in the spleen compared to wild-type mice. However, TGF-b unresponsiveness failed to restore effector functions of CD8 + T cells isolated from muscle tissue. Histological examination of skeletal muscle from T. cruziinfected DNRII mice revealed an extensive cellular infiltrate, and DNRII mice displayed higher susceptibility to infection. Overall, while TGF-b does not appear to be responsible for CD8 + T cell unresponsiveness in peripheral tissue in T. cruzi-infected mice, these data suggest a role for TGF-b in control of immunopathology in response to T. cruzi infection.

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Transforming growth factor-beta: An important role in CD4⁺CD25⁺regulatory T cells and immune tolerance

Cited by 71 publications

References 72 publications

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

In vitro induction of regulatory T cells by anti-CD3 antibody in humans

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

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Transforming growth factor-beta: An important role in CD4+CD25+regulatory T cells and immune tolerance

Cited by 71 publications

References 72 publications

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

RNA interference-mediated silencing of Foxo3 in antigen-presenting cells as a strategy for the enhancement of DNA vaccine potency

In vitro induction of regulatory T cells by anti-CD3 antibody in humans

TGF‐β regulates pathology but not tissue CD8+ T cell dysfunction during experimental Trypanosoma cruzi infection

Contact Info

Product

Resources

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Transforming growth factor-beta: An important role in CD4⁺CD25⁺regulatory T cells and immune tolerance

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection