Disruption of T Cell Homeostasis in Mice Expressing a T Cell–Specific Dominant Negative Transforming Growth Factor β II Receptor

Lucas, Paul A.; Kim, Seong‐Jin; Melby, Spencer J.; Gress, Ronald E.

doi:10.1084/jem.191.7.1187

Cited by 233 publications

(193 citation statements)

References 59 publications

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“…However, in the current studies CD8 + T cells comprised 80% of the splenic lymphocyte compartment in T. cruzi-infected DNRII mice with no selective expansion of the dominant TSKB20-specific CD8 + T cell population. These data reflect the preferential inhibition of homeostatic CD8 + T cell proliferation by TGF-b in aged DNRII mice [8]. While expansion of very low frequency CD8 + T cells recognizing yet unidentified T .cruzi peptides in infected DNRII mice may also occur, it seems unlikely that this would result in CD8 + T cells becoming the majority lymphocyte population in these mice.…”

Section: Discussionmentioning

confidence: 73%

“…The early lethality of TGF-b -/-mice makes this an unsuitable model in which to study infectious diseases. The role of TGF-b in regulating T cell responses has recently been studied using mouse strains expressing a dominant negative TGF-b type II receptor (DNRII) under a CD2 promoter, selectively rendering T cells unresponsive to TGF-b [8]. DNRII mice exhibit significant proliferation of CD8 + T cells over time, establishing a role for TGF-b in maintaining CD8 + T cell homeostasis [8].…”

Section: Introductionmentioning

confidence: 99%

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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: 73%

Section: Introductionmentioning

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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“…This strongly suggests that factors other than IL-10 are involved in the regulation of peripheral T cell numbers. Indeed, spontaneous autoimmune disease and disruption of T cell homeostasis were recently described in mice transgenic for a T celltargeted dominant negative TGF-␤ receptor (42,43). It is worth pointing out, however, that whatever the cellular interactions or mechanisms that delay the development of disease in IL-10°mice, they are disrupted in the transfer experiments presented here.…”

Section: Figurementioning

confidence: 55%

CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

Annacker

Pimenta-Araujo

Burlen-Defranoux

et al. 2001

The Journal of Immunology

496

395

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The mechanisms by which the immune system achieves constant T cell numbers throughout life, thereby controlling autoaggressive cell expansions, are to date not completely understood. Here, we show that the CD25+ subpopulation of naturally activated (CD45RBlow) CD4 T cells, but not CD25− CD45RBlow CD4 T cells, inhibits the accumulation of cotransferred CD45RBhigh CD4 T cells in lymphocyte-deficient mice. However, both CD25+ and CD25− CD45RBlow CD4 T cell subpopulations contain regulatory cells, since they can prevent naive CD4 T cell-induced wasting disease. In the absence of a correlation between disease and the number of recovered CD4+ cells, we conclude that expansion control and disease prevention are largely independent processes. CD25+ CD45RBlow CD4 T cells from IL-10-deficient mice do not protect from disease. They accumulate to a higher cell number and cannot prevent the expansion of CD45RBhigh CD4 T cells upon transfer compared with their wild-type counterparts. Although CD25+ CD45RBlow CD4 T cells are capable of expanding when transferred in vivo, they reach a homeostatic equilibrium at lower cell numbers than CD25− CD45RBlow or CD45RBhigh CD4 T cells. We conclude that CD25+ CD45RBlow CD4 T cells from nonmanipulated mice control the number of peripheral CD4 T cells through a mechanism involving the production of IL-10 by regulatory T cells.

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“…Genetic disruption of TGF-b signaling in T cells by overexpression of a dominant-negative TGF-b type II receptor (DNRIITg), conditional deletion of the TGF-b type II receptor, or inactivation of the gene encoding Smad3, alters the sensitivity of T cells to the inhibitory effects of TGF-b and leads to aberrant T cell responses [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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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...

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Disruption of T Cell Homeostasis in Mice Expressing a T Cell–Specific Dominant Negative Transforming Growth Factor β II Receptor

Cited by 233 publications

References 59 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

CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

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

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Disruption of T Cell Homeostasis in Mice Expressing a T Cell–Specific Dominant Negative Transforming Growth Factor β II Receptor

Cited by 233 publications

References 59 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

CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

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

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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

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