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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-7-induced homing receptor modulation.T cells were cultured in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM) and the expression of several homing receptors (A), CXCR4 (B) and CCR9 (C) was analyzed by flow cytometry after 36 hours of culture. Bars represent the mean ± SD of two independent experiments (* p≤0.05; by t test. IL-7/DMSO vs IL-7/DMH1).
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pone.0131453.g007: DMH1 effects on IL-7-induced homing receptor modulation.T cells were cultured in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM) and the expression of several homing receptors (A), CXCR4 (B) and CCR9 (C) was analyzed by flow cytometry after 36 hours of culture. Bars represent the mean ± SD of two independent experiments (* p≤0.05; by t test. IL-7/DMSO vs IL-7/DMH1).

Mentions: Given that IL-7 has been described to modulate the expression of several homing receptors in T cells [29], we analyzed whether autocrine BMP signaling could be mediating in this process. DMH1 treatment showed no effects in the regulation of the lymph node homing receptors L-selectin/CD62L and the integrins α4/CD49d, αL/CD11a and β2/CD18 (Fig 7A). Similar results were obtained for the chemokine receptor CCR7, shown to be important for lymphocyte migration towards lymph nodes (Fig 7A). According to previous results, IL-7 induced the upregulation of the chemokine receptor CXCR4. Nevertheless, CXCR4 induction was completely abrogated in the presence of DMH1 (Fig 7B). In the same line, IL-7 induction of the gut homing receptor CCR9 was also abolished by canonical BMP signaling inhibition (Fig 7B), showing a very specific impact of this inhibitor on the regulation of homing receptors provoked by IL-7.


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-7-induced homing receptor modulation.T cells were cultured in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM) and the expression of several homing receptors (A), CXCR4 (B) and CCR9 (C) was analyzed by flow cytometry after 36 hours of culture. Bars represent the mean ± SD of two independent experiments (* p≤0.05; by t test. IL-7/DMSO vs IL-7/DMH1).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131453.g007: DMH1 effects on IL-7-induced homing receptor modulation.T cells were cultured in media alone or supplemented with IL-7 and DMSO or IL-7 and DMH1 (40 μM) and the expression of several homing receptors (A), CXCR4 (B) and CCR9 (C) was analyzed by flow cytometry after 36 hours of culture. Bars represent the mean ± SD of two independent experiments (* p≤0.05; by t test. IL-7/DMSO vs IL-7/DMH1).
Mentions: Given that IL-7 has been described to modulate the expression of several homing receptors in T cells [29], we analyzed whether autocrine BMP signaling could be mediating in this process. DMH1 treatment showed no effects in the regulation of the lymph node homing receptors L-selectin/CD62L and the integrins α4/CD49d, αL/CD11a and β2/CD18 (Fig 7A). Similar results were obtained for the chemokine receptor CCR7, shown to be important for lymphocyte migration towards lymph nodes (Fig 7A). According to previous results, IL-7 induced the upregulation of the chemokine receptor CXCR4. Nevertheless, CXCR4 induction was completely abrogated in the presence of DMH1 (Fig 7B). In the same line, IL-7 induction of the gut homing receptor CCR9 was also abolished by canonical BMP signaling inhibition (Fig 7B), showing a very specific impact of this inhibitor on the regulation of homing receptors provoked by IL-7.

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