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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

Canonical BMP pathway and IL-7 signaling.(A) Expression of BMP2/4 and BMP6 was determined by flow cytometry at the indicated time points in T cells cultured in media alone (grey histograms) or in the presence of IL-7 (5 ng/ml) (black histograms). Grey filled histograms represent isotype control stainings. A representative experiment out of four is shown. (B) Differential expression of phosphorylated Smad-1/5/8 (pBR-Smad) analyzed by flow cytometry in naive CD4+ T cells after 11 days of culture in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM). Percentages represent the increment relative to cultures in media alone. One representative of three independent experiments is shown.
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pone.0131453.g005: Canonical BMP pathway and IL-7 signaling.(A) Expression of BMP2/4 and BMP6 was determined by flow cytometry at the indicated time points in T cells cultured in media alone (grey histograms) or in the presence of IL-7 (5 ng/ml) (black histograms). Grey filled histograms represent isotype control stainings. A representative experiment out of four is shown. (B) Differential expression of phosphorylated Smad-1/5/8 (pBR-Smad) analyzed by flow cytometry in naive CD4+ T cells after 11 days of culture in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM). Percentages represent the increment relative to cultures in media alone. One representative of three independent experiments is shown.

Mentions: Our results pointed out a tight relationship between autocrine BMP signaling and activation-induced T cell proliferation. Hence, we next wondered whether the BMP signaling pathway could be acting in a different process also associated with proliferation. In this regard, IL-7 is a well known key factor regulating the homeostasis of naive and memory T cells and capable of inducing the so-called homeostatic proliferation of both subsets [20]. When naive T cells were cultured in the presence of IL-7, production of BMP ligands BMP2/4 and BMP6 was progressively induced throughout the culture (Fig 5A). Expression of these ligands showed a homogeneous pattern suggesting that the majority of the cells were responding to IL-7 stimulation in terms of BMP production. Accordingly, levels of pBR-Smads were increased by 55% compared to cells cultured in media alone at day 11, while addition of the DMH1 inhibitor mostly inhibited BR-Smad phophorylation (Fig 5B).


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)

Canonical BMP pathway and IL-7 signaling.(A) Expression of BMP2/4 and BMP6 was determined by flow cytometry at the indicated time points in T cells cultured in media alone (grey histograms) or in the presence of IL-7 (5 ng/ml) (black histograms). Grey filled histograms represent isotype control stainings. A representative experiment out of four is shown. (B) Differential expression of phosphorylated Smad-1/5/8 (pBR-Smad) analyzed by flow cytometry in naive CD4+ T cells after 11 days of culture in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM). Percentages represent the increment relative to cultures in media alone. One representative of three independent experiments is shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481406&req=5

pone.0131453.g005: Canonical BMP pathway and IL-7 signaling.(A) Expression of BMP2/4 and BMP6 was determined by flow cytometry at the indicated time points in T cells cultured in media alone (grey histograms) or in the presence of IL-7 (5 ng/ml) (black histograms). Grey filled histograms represent isotype control stainings. A representative experiment out of four is shown. (B) Differential expression of phosphorylated Smad-1/5/8 (pBR-Smad) analyzed by flow cytometry in naive CD4+ T cells after 11 days of culture in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM). Percentages represent the increment relative to cultures in media alone. One representative of three independent experiments is shown.
Mentions: Our results pointed out a tight relationship between autocrine BMP signaling and activation-induced T cell proliferation. Hence, we next wondered whether the BMP signaling pathway could be acting in a different process also associated with proliferation. In this regard, IL-7 is a well known key factor regulating the homeostasis of naive and memory T cells and capable of inducing the so-called homeostatic proliferation of both subsets [20]. When naive T cells were cultured in the presence of IL-7, production of BMP ligands BMP2/4 and BMP6 was progressively induced throughout the culture (Fig 5A). Expression of these ligands showed a homogeneous pattern suggesting that the majority of the cells were responding to IL-7 stimulation in terms of BMP production. Accordingly, levels of pBR-Smads were increased by 55% compared to cells cultured in media alone at day 11, while addition of the DMH1 inhibitor mostly inhibited BR-Smad phophorylation (Fig 5B).

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