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

Kullberg, Marika C.; Hay, Valerie; Cheever, Allen W.; Mamura, Mizuko; Sher, Alan; Letterio, John J.; Shevach, Ethan M.; Piccirillo, Ciriaco A.

doi:10.1002/eji.200526106

Cited by 110 publications

(86 citation statements)

References 42 publications

(80 reference statements)

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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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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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“…In a few in vivo models, expression of IL-10 or TGF-β specifically in T reg cells is required for T reg cell function [51][52][53] . However, in some other situations, the source of these suppressive cytokines is not limited to T reg cells 37,54,55 .…”

Section: T Reg Cell-derived Suppressor Moleculesmentioning

confidence: 99%

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

2008

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The function of regulatory T cells (T reg cells) has been attributed to a growing number of diverse pathways, molecules and processes. Seemingly contradictory conclusions regarding the mechanisms underlying T reg cell suppressive activity have revitalized skeptics in the field who challenge the core validity of the idea of T reg cells as central immune regulators. However, we note that a consensus may be emerging from the data: that multiple T reg cell functions act either directly or indirectly at the site of antigen presentation to create a regulatory milieu that promotes bystander suppression and infectious tolerance. Thus, the versatility and adaptability of the Foxp3 + T reg cells may in fact be the best argument that these cells are 'multitalented masters of immune regulation'.Armed with the potential to destroy invading microorganisms and stop aberrant outgrowth of tumor cells, the immune system has extensive built-in mechanisms for preventing attack of healthy self tissues. The first line of such 'self-tolerance' is the elimination of selfreactive T lymphocytes and B lymphocytes during negative selection in the thymus and bone marrow, respectively. However, there has long been a belief that the immune system must have peripheral mechanisms in place to deal with immune cells that 'escape' central tolerance. For almost 40 years, immunologists have postulated the existence of suppressor T cells that police the immune system to avert unwanted immune responses 1-3 . However, that phenomenology was cast into doubt as various labs presented unique, hard-to-reproduce systems, each with complexities and idiosyncrasies that raised credibility issues. This situation was not unlike the early years of cytokine biology, during which dozens of activities were found in sera and cell supernatants without consistent molecular or biochemical 'signatures'. Fortunately, as biochemistry and the molecular biology revolution rescued the field of cytokine biology by identifying genes and biochemical structures tied to the varied biologic activities, the identification of a constellation of cell surface, transcriptional and biochemical markers that uniquely mark 'regulatory' T cells (T reg cells) has made possible a rebirth of the suppressor T cell field over the past decade.The realization that T reg cells have a unique surface expression profile incorporating CD25, CD62L and specific CD45 isoforms 4-6 , together with the identification of the T reg cellspecific transcription factor Foxp3, catapulted T reg cells from a rare CD4 + T cell subset to

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“…Our previous studies failed to define a role for T reg produced TGF-b in our standard in vitro suppression assay. Foxp3 + T reg from TGF-bdeficient mice were also capable of suppressing the induction of colitis by Foxp3 -effector cells in vivo [13]. In view of the studies in the mouse demonstrating that TGF-b is a potent inducer of Foxp3 + T reg , it remained possible that some of the purported suppressive effects of T reg produced TGF-b were secondary to its capacity to induce T reg de novo and not secondary to its suppressor effector functions.…”

Section: What Is the Function Of T Reg Cell-produced Tgf-b?mentioning

confidence: 99%

The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

Shevach¹,

et al. 2008

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Stimulation of mouse CD4+ T cells in the presence of TGF‐β results in the expression of Foxp3 and induction of Treg function. Stimulation of human CD4+ T cells under similar conditions results in the expression of Foxp3, but the cells lack regulatory cell function. TGF‐β expressed on the surface of Treg also induces Foxp3 expression and Treg function in responder cells. Both of these mechanisms may play a role in vivo in the induction of antigen‐specific extra‐thymic Treg. See accompanying commentary:

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

Cited by 110 publications

References 42 publications

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

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

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

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

Cited by 110 publications

References 42 publications

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

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

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

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Product

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

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

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