Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF-β Signaling

Nelson, Brad H.; Martyak, Timothy P.; Thompson, Lucas; Moon, James J.; Wang, Tongwen

doi:10.4049/jimmunol.170.11.5563

Cited by 33 publications

(18 citation statements)

References 79 publications

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“…Thus, T cells that fail to cycle after stimulation were found to be similarly refractory to the mitogenic effects of IL-2 (23,24). Likewise, stimulation of T cells with TGF-␤ blocks IL-2-mediated proliferation through direct effects on cell cycle genes (25,26). As in this study, the STAT5 signaling pathway remains intact; however, downstream elements regulated by STAT5, including cyclins and c-Myc, are not induced.…”

Section: Cd4mentioning

confidence: 46%

Uncoupling of IL-2 Signaling from Cell Cycle Progression in Naive CD4+ T Cells by Regulatory CD4+CD25+ T Lymphocytes

Duthoit

Mekala

Alli

et al. 2005

The Journal of Immunology

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Prior reports have shown that CD4+CD25+ regulatory T cells suppress naive T cell responses by inhibiting IL-2 production. In this report, using an Ag-specific TCR transgenic system, we show that naive T cells stimulated with cognate Ag in the presence of preactivated CD4+CD25+ T cells also become refractory to the mitogenic effects of IL-2. T cells stimulated in the presence of regulatory T cells up-regulated high affinity IL-2R, but failed to produce IL-2, express cyclins or c-Myc, or exit G0-G1. Exogenous IL-2 failed to break the mitotic block, demonstrating that the IL-2 production failure was not wholly responsible for the proliferation defect. This IL-2 unresponsiveness did not require the continuous presence of CD4+CD25+ regulatory T cells. The majority of responder T cells reisolated after coculture with regulatory cells failed to proliferate in response to IL-2, but were not anergic and proliferated in response to Ag. The mitotic block was also dissociated from the antiapoptotic effects of IL-2, because IL-2 still promoted the survival of T cells that had been cocultured with CD4+CD25+ T cells. IL-2-induced STAT5 phosphorylation in the cocultured responder cells was intact, implying that the effects of the regulatory cells were downstream of receptor activation. Our results therefore show that T cell activation in the presence of CD4+CD25+ regulatory T cells can induce an alternative stimulation program characterized by up-regulation of high affinity IL-2R, but a failure to produce IL-2, and uncoupling of the mitogenic and antiapoptotic effects of IL-2.

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Section: Cd4mentioning

confidence: 46%

Uncoupling of IL-2 Signaling from Cell Cycle Progression in Naive CD4+ T Cells by Regulatory CD4+CD25+ T Lymphocytes

Duthoit

Mekala

Alli

et al. 2005

The Journal of Immunology

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“…In one study, undivided activated T cells that were isolated and stimulated with IL-2 were found to phosphorylate Akt and up-regulate Bcl-2 and Bcl-xL, but failed to proliferate (19). Similarly, treatment of T cells with TGF-␤ blocks IL-2-induced proliferation, but not the anti-apoptotic effects of IL-2 (22).…”

Section: Discussionmentioning

confidence: 99%

Antigen Nonspecific Suppression of T Cell Responses by Activated Stimulation-Refractory CD4+ T Cells

Duthoit

Nguyen

Geiger

2004

The Journal of Immunology

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Several classes of anergic T cells are capable of suppressing naive T cell proliferation and thereby limiting immune responses. Activated T cells, although not anergic, are transiently refractory to restimulation with Ag. We examine in this study whether activated refractory murine T cells can also suppress naive T cell responses. We find that they can, and that they exhibit many of the suppressive properties of anergic T cells. The activated cells strongly diminish Ag-mediated T cell proliferation, an activity that correlates with their refractory period. Suppression is independent of APC numbers and requires cell contact or proximity. Naive T cells stimulated in the presence of activated refractory cells up-regulate CD25 and CD69, but fail to produce IL-2. The addition of IL-2 to culture medium, however, does not prevent the suppression, which is therefore not solely due to the absence of this growth factor. Persistence of the suppressor cells is also not essential. T cells stimulated in their presence and then isolated from them and cultured do not divide. The suppressive cells, however, do not confer a refractory or anergic state on the target T lymphocytes, which can fully respond to antigenic stimulation if removed from the suppressors. Our results therefore provide evidence that activated T cells act as transient suppressor cells, severely constraining bystander T cell stimulation and thereby restricting their response. These results have potentially broad implications for the development and regulation of immune responses.

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“…Upon activation of the PD-1 or TGFb1 pathways, targeted cells present in the bulk population of splenocytes modulate the expression of receptors for stimulatory lymphokines, such as IL-12R, and downregulate the expression of the STAT5a and STAT5b gene, rendering this molecular complex inefficient in transducing the proliferation signal of type I cytokines [28,29].…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway

et al. 2005

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Bone marrow mesenchymal progenitor cells (BMSC) are used for regenerating tissues of mesodermal origin, as well as tissues of different embryological derivation. Experimental evidence shows that BMSC are able to suppress the activation of the immune response by mechanisms that are still not completely understood. Thus far, in vitro studies carried using human or mouse cells indicate that autologous or allogeneic BMSC strongly suppress proliferation of T lymphocytes, triggered by cellular stimuli, nonspecific mitogenic stimuli, or antigenic peptides. Using cell proliferation and blocking assays, we demonstrated that BMSC inhibited the activation of murine splenocytes, T, and B lymphocytes. Direct contact of BMSC and target cells in a cognate fashion determined the inhibition of cell proliferation via engagement of the inhibitory molecule programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2, leading the target cells to modulate the expression of different cytokine receptors and transduction molecules for cytokine signaling. Soluble factors present on supernatants of BMSC cultures were effective in suppressing proliferation of B cells to a mitogenic stimulus. Taken together, these results highlight the complexity of the role of BMSC in regulating the immune response, asserting the possibility of their therapeutic application in transplantation and autoimmune diseases.

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Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF-β Signaling

Cited by 33 publications

References 79 publications

Uncoupling of IL-2 Signaling from Cell Cycle Progression in Naive CD4+ T Cells by Regulatory CD4+CD25+ T Lymphocytes

Uncoupling of IL-2 Signaling from Cell Cycle Progression in Naive CD4+ T Cells by Regulatory CD4+CD25+ T Lymphocytes

Antigen Nonspecific Suppression of T Cell Responses by Activated Stimulation-Refractory CD4+ T Cells

Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway

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