Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated.

Diebold, Ronald J.; Eis, Michael J.; Yin, Moying; Ormsby, Ilona; Boivin, Greg P.; Darrow, Bruce; Saffitz, Jeffrey E.; Doetschman, Thomas

doi:10.1073/pnas.92.26.12215

Cited by 254 publications

(184 citation statements)

References 16 publications

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…TGF-b1 -/-and Smad3 -/-mice (both on the C57BL/6ÂSv129 genetic background) were generated by targeted gene disruption in murine embryonic stem cells by homologous recombination as previously described [39,40]. All mice were bred and maintained in a specific pathogen-free animal facility.…”

Section: Methodsmentioning

confidence: 99%

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

View full text Add to dashboard Cite

Naturally occurring CD4 + CD25 + regulatory T cells (Treg) are potent suppressors of CD4 + and CD8 + T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4 + CD25 + Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-b1 and effector T cell responsiveness to TGF-b in CD4 + CD25 + T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4 + CD25 + Treg cells from either TGF-b1 +/+ or neonatal TGF-b1 -/-mice can suppress the incidence and severity of IBD as well as colonic IFN-c mRNA expression induced by WT CD4 + CD25 -effector T cells. Furthermore, TGF-b-resistant Smad3 -/-CD4 + CD25 + Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3 -/-CD4 + CD25 -effector T cells. Finally, anti-TGF-b treatment exacerbates the colitogenic potential of CD4 + CD25 -effector T cells in the absence of CD4 + CD25 + Treg cells.Together, these data demonstrate that in certain situations CD4 + CD25 + T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-b1 or effector T cell/Treg cell responsiveness to TGF-b via Smad3. IntroductionCD25 (IL-2Ra chain)-expressing CD4 + T cells, which constitute 5-10% of normal CD4 + T cells, play a critical role in the induction and maintenance of peripheral tolerance [1,2]. These naturally occurring CD4 + CD25 + regulatory T (Treg) cells consist of an anergic lymphocyte population with potent immunosuppressive functions in vivo, as the depletion of CD25-expressing CD4 + T cells correlates with increased immunity to tumors, grafts and intracellular pathogens and provokes the induction of multiple inflammatory diseases including autoimmmune gastritis (AIG) and inflammatory bowel disease (IBD) [3,4]. Currently, the mechanism(s) by which CD4 + CD25 + Treg cells mediate suppression in vitro and in vivo is unclear. Following TCR activation, CD4 + CD25 + Treg cells suppress the in vitro proliferation and cytokine production of CD4 + and CD8 + T cells in an antigen nonspecific, but contact-dependent manner that does not appear to involve modulation of APC function [5][6][7]. The role of regulatory cytokines in CD4 + CD25 + Treg cell control of inflammation in vivo appears to be tissue and/ or context-dependent. While CD4 + CD25 + Treg cells from IL-4 -/-and IL-10 -/-mice are as effective as WT CD4 + CD25 + T cells in mediating suppression of AIG, CD4 + CD25 + Treg cells from IL-10 -/-mice cannot control IBD induced by antigen-experienced effector T cells [8,9]. Similarly, IL-10 -/-CD4 + CD25 + Treg cells, in contrast to WT cells, fail to attenuate effector T cell responses to Leishmania major in resistant C57BL/6 mice [10].TGF-b1 is a potently suppressive cytokine that plays a critical role in the regulation of immune function, a...

show abstract

Section: Methodsmentioning

confidence: 99%

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The inflammatory disease observed in heart and lung in TGF-␤1 Ϫ/Ϫ mice (of non-BALB/c backgrounds) is dependent upon Th cells, since CD4 ϩ T cell-deficient TGF-␤1 Ϫ/Ϫ mice do not develop these inflammatory pathologies (21,34). Thus, we reasoned that CD4 ϩ T cells would be involved in the liver pathogenesis observed in BALB/c-TGF-␤1 Ϫ/Ϫ mice.…”

Section: Balb/c-tgf-␤1 ϫ/ϫ Livers Have Large Numbers Of Activated Th1mentioning

confidence: 99%

Genetic Regulation of Autoimmune Disease: BALB/c Background TGF-β1-Deficient Mice Develop Necroinflammatory IFN-γ-Dependent Hepatitis

Gorham¹,

Lin²,

Sung³

et al. 2001

The Journal of Immunology

114

View full text Add to dashboard Cite

Autoimmune hepatitis (AIH) in humans arises spontaneously in genetically susceptible individuals and is associated with the presence of Th1 cells in the liver. The understanding of AIH has advanced more slowly than that of other organ-specific autoimmune diseases, however, largely because of the lack of an appropriate animal model. We now describe a new mouse model characterized by spontaneous development of necroinflammatory hepatitis that is restricted by genetic background. Mice deficient in the immunomodulatory cytokine TGF-β1 were extensively back-bred to the BALB/c background. The BALB/c background dramatically modified the phenotype of TGF-β1−/− mice: specifically, BALB/c-TGF-β1−/− mice developed a lethal necroinflammatory hepatitis that was not observed in TGF-β1−/− mice on a different genetic background. BALB/c background TGF-β1−/− livers contained large numbers of activated CD4+ T cells that produced large quantities of IFN-γ, but little IL-4, identifying them as Th1 cells. BALB/c background TGF-β1−/−/IFN-γ−/− double knockout mice, generated by cross-breeding, did not develop necroinflammatory hepatitis, demonstrating that IFN-γ is mechanistically required for its pathogenesis. This represents the first murine model of hepatitis that develops spontaneously, is restricted by genetic background, and is dependent upon the Th1 cytokine IFN-γ, and that thus recapitulates these important aspects of AIH.

show abstract

“…These mice develop a rapid wasting syndrome, which leads to death at the age of 3-4 wk (1). The autoimmune phenotype of TGF-␤1 Ϫ/Ϫ mice has been largely ascribed to the presence of activated CD4 ϩ T cells (2). However, the precise mechanism of spontaneous T cell activation in the absence of TGF-␤1 remains to be elucidated.…”

mentioning

confidence: 99%

Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells

Huber¹,

Schramm²,

Lehr

et al. 2004

The Journal of Immunology

372

246

View full text Add to dashboard Cite

Data regarding the role of TGF-β for the in vivo function of regulatory CD4+CD25+ T cells (Treg) are controversial. A transgenic mouse model with impaired TGF-β signaling specifically in T cells was used to assess the role of endogenous TGF-β for the in vivo function of CD4+CD25+ Treg in a murine model of colitis induced by dextran sulfate. Transfer of wild-type, but not transgenic CD4+CD25+ Treg was found to suppress colitis in wild-type mice. In addition, by transferring CFSE-labeled CD4+CD25+ Treg we could demonstrate that endogenous TGF-β promotes the expansion of CD4+CD25+ Treg in vivo. Transgenic mice themselves developed reduced numbers of peripheral CD4+CD25+ Treg and were more susceptible to the induction of colitis, which could be prevented by the transfer of wild-type Treg. These data indicate that TGF-β signaling in CD4+CD25+ Treg is required for their in vivo expansion and suppressive capacity.

show abstract

Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated.

Abstract: Transforming growth factor 31 (TGFj81) -

Cited by 254 publications

References 16 publications

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

Genetic Regulation of Autoimmune Disease: BALB/c Background TGF-β1-Deficient Mice Develop Necroinflammatory IFN-γ-Dependent Hepatitis

Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells

Contact Info

Product

Resources

About

Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated.

Abstract: Transforming growth factor 31 (TGFj81) -

Cited by 254 publications

References 16 publications

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

Genetic Regulation of Autoimmune Disease: BALB/c Background TGF-β1-Deficient Mice Develop Necroinflammatory IFN-γ-Dependent Hepatitis

Cutting Edge: TGF-β Signaling Is Required for the In Vivo Expansion and Immunosuppressive Capacity of Regulatory CD4+CD25+ T Cells

Contact Info

Product

Resources

About

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation