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The BMP Pathway Participates in Human Naive CD4+ T Cell Activation and Homeostasis.

Martínez VG, Sacedón R, Hidalgo L, Valencia J, Fernández-Sevilla LM, Hernández-López C, Vicente A, Varas A - PLoS ONE (2015)

Bottom Line: Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling.Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis.Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain.

ABSTRACT
Bone Morphogenetic Proteins (BMPs) form a group of secreted factors that belongs to the TGF-β superfamily. Among different roles in a number of immune cell types, BMPs are known to regulate T cell development within the thymus, although the role of BMP signaling in human mature T cells remains elusive. In this study, we demonstrate that canonical BMP signaling is necessary during two critical events that regulate the size and function of human naive CD4+ T cell population: activation and homeostasis. Upon stimulation via TCR, naive CD4+ T cells upregulate the expression of BMP ligands triggering canonical BMP signaling in CD25+ cells. Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling. Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis. Moreover, upregulation of two critical receptors for T cell homeostasis, CXCR4 and CCR9, triggered by IL-7 is also abrogated in the absence of BMP signaling. Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application.

No MeSH data available.


Related in: MedlinePlus

DMH1 effects on IL-2 expression.TCR-induced IL-2 production by T cells in the presence of DMSO or DMH1 at day 4 (A) and 2 (B, left graph). (B, right graph) mRNA expression for IL2 after 2 days of activation. GNB2L1 was used as endogenous control. Means ± SD of three to five independent experiments performed in duplicates are shown (* p≤0.05; ** p≤0.01; by t test). (C) Proliferation rate measured by CFSE loss in T cells after 4 days of TCR stimulation with DMSO, DMH1 alone or DMH1 supplemented with the indicated doses of rhIL-2. Bars represent the means ± SD of three independent experiments (* p≤0.05; by t test).
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pone.0131453.g004: DMH1 effects on IL-2 expression.TCR-induced IL-2 production by T cells in the presence of DMSO or DMH1 at day 4 (A) and 2 (B, left graph). (B, right graph) mRNA expression for IL2 after 2 days of activation. GNB2L1 was used as endogenous control. Means ± SD of three to five independent experiments performed in duplicates are shown (* p≤0.05; ** p≤0.01; by t test). (C) Proliferation rate measured by CFSE loss in T cells after 4 days of TCR stimulation with DMSO, DMH1 alone or DMH1 supplemented with the indicated doses of rhIL-2. Bars represent the means ± SD of three independent experiments (* p≤0.05; by t test).

Mentions: Secretion of IL-2 by T cells during activation is crucial for their own proliferation. We therefore determined the production of IL-2 in these cultures finding that DMH1 treatment had a negative impact on IL-2 levels after 4 days of culture. Specifically, canonical BMP signaling blockade affected IL-2 production in a dose-dependent manner reaching a maximum of 80% of inhibition when the highest dose of DMH1 was used (Fig 4A). In addition, IL2 transcription as well as IL-2 protein secretion were impaired by DMH1 treatment as soon as 2 days after TCR stimulation (Fig 4B). On the contrary, no effects in the expression of CD25 were observed at this time point (data not shown). To better understand the role of IL-2 in the inhibition induced by DMH1, rhIL-2 was added at different doses together with DMH1 and the proliferative response was measured by CFSE loss. As expected, increasing concentrations of rhIL-2 partially counteracted the inhibiting effects of DMH1, being the highest dose of rhIL-2 able to fully restore the proliferative response of T cells (Fig 4C).


The BMP Pathway Participates in Human Naive CD4+ T Cell Activation and Homeostasis.

Martínez VG, Sacedón R, Hidalgo L, Valencia J, Fernández-Sevilla LM, Hernández-López C, Vicente A, Varas A - PLoS ONE (2015)

DMH1 effects on IL-2 expression.TCR-induced IL-2 production by T cells in the presence of DMSO or DMH1 at day 4 (A) and 2 (B, left graph). (B, right graph) mRNA expression for IL2 after 2 days of activation. GNB2L1 was used as endogenous control. Means ± SD of three to five independent experiments performed in duplicates are shown (* p≤0.05; ** p≤0.01; by t test). (C) Proliferation rate measured by CFSE loss in T cells after 4 days of TCR stimulation with DMSO, DMH1 alone or DMH1 supplemented with the indicated doses of rhIL-2. Bars represent the means ± SD of three independent experiments (* p≤0.05; by t test).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4481406&req=5

pone.0131453.g004: DMH1 effects on IL-2 expression.TCR-induced IL-2 production by T cells in the presence of DMSO or DMH1 at day 4 (A) and 2 (B, left graph). (B, right graph) mRNA expression for IL2 after 2 days of activation. GNB2L1 was used as endogenous control. Means ± SD of three to five independent experiments performed in duplicates are shown (* p≤0.05; ** p≤0.01; by t test). (C) Proliferation rate measured by CFSE loss in T cells after 4 days of TCR stimulation with DMSO, DMH1 alone or DMH1 supplemented with the indicated doses of rhIL-2. Bars represent the means ± SD of three independent experiments (* p≤0.05; by t test).
Mentions: Secretion of IL-2 by T cells during activation is crucial for their own proliferation. We therefore determined the production of IL-2 in these cultures finding that DMH1 treatment had a negative impact on IL-2 levels after 4 days of culture. Specifically, canonical BMP signaling blockade affected IL-2 production in a dose-dependent manner reaching a maximum of 80% of inhibition when the highest dose of DMH1 was used (Fig 4A). In addition, IL2 transcription as well as IL-2 protein secretion were impaired by DMH1 treatment as soon as 2 days after TCR stimulation (Fig 4B). On the contrary, no effects in the expression of CD25 were observed at this time point (data not shown). To better understand the role of IL-2 in the inhibition induced by DMH1, rhIL-2 was added at different doses together with DMH1 and the proliferative response was measured by CFSE loss. As expected, increasing concentrations of rhIL-2 partially counteracted the inhibiting effects of DMH1, being the highest dose of rhIL-2 able to fully restore the proliferative response of T cells (Fig 4C).

Bottom Line: Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling.Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis.Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain.

ABSTRACT
Bone Morphogenetic Proteins (BMPs) form a group of secreted factors that belongs to the TGF-β superfamily. Among different roles in a number of immune cell types, BMPs are known to regulate T cell development within the thymus, although the role of BMP signaling in human mature T cells remains elusive. In this study, we demonstrate that canonical BMP signaling is necessary during two critical events that regulate the size and function of human naive CD4+ T cell population: activation and homeostasis. Upon stimulation via TCR, naive CD4+ T cells upregulate the expression of BMP ligands triggering canonical BMP signaling in CD25+ cells. Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling. Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis. Moreover, upregulation of two critical receptors for T cell homeostasis, CXCR4 and CCR9, triggered by IL-7 is also abrogated in the absence of BMP signaling. Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application.

No MeSH data available.


Related in: MedlinePlus