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Inhibins tune the thymocyte selection process by regulating thymic stromal cell differentiation.

Carbajal-Franco E, de la Fuente-Granada M, Alemán-Muench GR, García-Zepeda EA, Soldevila G - J Immunol Res (2015)

Bottom Line: Inhibins and Activins are members of the TGF-β superfamily that regulate the differentiation of several cell types.These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system.As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 México, DF, Mexico.

ABSTRACT
Inhibins and Activins are members of the TGF-β superfamily that regulate the differentiation of several cell types. These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system. We have previously demonstrated that Inhibins are the main Activin ligands expressed in the murine thymus and that they regulate thymocyte differentiation, promoting the DN3-DN4 transition and the selection of SP thymocytes. As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function. Here, we demonstrate that, in the absence of Inhibins, thymic conventional dendritic cells display reduced levels of MHC Class II (MHCII) and CD86. In addition, the ratio between cTECs and mTECs was affected, indicating that mTEC differentiation was favoured and cTEC diminished in the absence of Inhibins. These changes appeared to impact thymocyte selection leading to a decreased selection of CD4SP thymocytes and increased generation of natural regulatory T cells. These findings demonstrate that Inhibins tune the T cell selection process by regulating both thymocyte and stromal cell differentiation.

No MeSH data available.


Related in: MedlinePlus

MHCII and CD86 expression in cDCs are reduced in thymus of Inhα−/− mice. (a) Representative flow cytometry dot plots and frequency of thymic cDCs defined as CD11c+ MHCII+ cells. For the MHCII (b), CD80 (c), and CD86 (c) expression, MFI was determined and reported as relative expression compared to Inhα+/+ mice. A significant reduction was observed for MHCII (P = 0.04) and CD86 (P = 0.04) expression in Inhα−/− thymic cDCs. One representative example of a total of 13 mice is shown (Inhα+/+, n = 6; Inhα−/−, n = 7) from 3 independent experiments. Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.
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fig2: MHCII and CD86 expression in cDCs are reduced in thymus of Inhα−/− mice. (a) Representative flow cytometry dot plots and frequency of thymic cDCs defined as CD11c+ MHCII+ cells. For the MHCII (b), CD80 (c), and CD86 (c) expression, MFI was determined and reported as relative expression compared to Inhα+/+ mice. A significant reduction was observed for MHCII (P = 0.04) and CD86 (P = 0.04) expression in Inhα−/− thymic cDCs. One representative example of a total of 13 mice is shown (Inhα+/+, n = 6; Inhα−/−, n = 7) from 3 independent experiments. Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.

Mentions: To further analyze hematopoietic derived thymic stromal cells, thymi were disaggregated through mechanical and enzymatic methods and analyzed by flow cytometry to identify cDCs, pDCs, and macrophages. In agreement with our previous data (Figure 1(b)), we observed a small reduction, although not significant, in the percentage and numbers of cDCs (CD11chi MHCIIhi) in Inhα−/− compared with Inhα+/+ mice (Figure 2(a)). Importantly, in this subpopulation we found a significant reduction in the mean fluorescence intensity (MFI) of MHCII when comparing Inhα−/− with Inhα+/+ (Figure 2(b)), suggesting that Inhibins may also be involved in the maturation of cDCs. Next, we analyzed the expression of costimulatory molecules CD80 and CD86, upregulated during DC maturation [31] and known to mediate the negative selection as well as the generation of nTregs (reviewed in [33]). As shown in Figure 2(c), CD86, but not CD80 levels, were significantly reduced in Inhα−/− compared to Inhα+/+ cDCs. The reduction of MHCII in the absence of Inhibins opposes previously reported data showing that Inhibin A is capable of preventing the upregulation of HLA-DR expression during human DC maturation in vitro [7]. However, it is worth noting that Activin ligands may exert different effects on immune cells under either inflammatory [34, 35] or steady state conditions [36], as the data shown here.


Inhibins tune the thymocyte selection process by regulating thymic stromal cell differentiation.

Carbajal-Franco E, de la Fuente-Granada M, Alemán-Muench GR, García-Zepeda EA, Soldevila G - J Immunol Res (2015)

MHCII and CD86 expression in cDCs are reduced in thymus of Inhα−/− mice. (a) Representative flow cytometry dot plots and frequency of thymic cDCs defined as CD11c+ MHCII+ cells. For the MHCII (b), CD80 (c), and CD86 (c) expression, MFI was determined and reported as relative expression compared to Inhα+/+ mice. A significant reduction was observed for MHCII (P = 0.04) and CD86 (P = 0.04) expression in Inhα−/− thymic cDCs. One representative example of a total of 13 mice is shown (Inhα+/+, n = 6; Inhα−/−, n = 7) from 3 independent experiments. Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4418002&req=5

fig2: MHCII and CD86 expression in cDCs are reduced in thymus of Inhα−/− mice. (a) Representative flow cytometry dot plots and frequency of thymic cDCs defined as CD11c+ MHCII+ cells. For the MHCII (b), CD80 (c), and CD86 (c) expression, MFI was determined and reported as relative expression compared to Inhα+/+ mice. A significant reduction was observed for MHCII (P = 0.04) and CD86 (P = 0.04) expression in Inhα−/− thymic cDCs. One representative example of a total of 13 mice is shown (Inhα+/+, n = 6; Inhα−/−, n = 7) from 3 independent experiments. Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.
Mentions: To further analyze hematopoietic derived thymic stromal cells, thymi were disaggregated through mechanical and enzymatic methods and analyzed by flow cytometry to identify cDCs, pDCs, and macrophages. In agreement with our previous data (Figure 1(b)), we observed a small reduction, although not significant, in the percentage and numbers of cDCs (CD11chi MHCIIhi) in Inhα−/− compared with Inhα+/+ mice (Figure 2(a)). Importantly, in this subpopulation we found a significant reduction in the mean fluorescence intensity (MFI) of MHCII when comparing Inhα−/− with Inhα+/+ (Figure 2(b)), suggesting that Inhibins may also be involved in the maturation of cDCs. Next, we analyzed the expression of costimulatory molecules CD80 and CD86, upregulated during DC maturation [31] and known to mediate the negative selection as well as the generation of nTregs (reviewed in [33]). As shown in Figure 2(c), CD86, but not CD80 levels, were significantly reduced in Inhα−/− compared to Inhα+/+ cDCs. The reduction of MHCII in the absence of Inhibins opposes previously reported data showing that Inhibin A is capable of preventing the upregulation of HLA-DR expression during human DC maturation in vitro [7]. However, it is worth noting that Activin ligands may exert different effects on immune cells under either inflammatory [34, 35] or steady state conditions [36], as the data shown here.

Bottom Line: Inhibins and Activins are members of the TGF-β superfamily that regulate the differentiation of several cell types.These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system.As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 México, DF, Mexico.

ABSTRACT
Inhibins and Activins are members of the TGF-β superfamily that regulate the differentiation of several cell types. These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system. We have previously demonstrated that Inhibins are the main Activin ligands expressed in the murine thymus and that they regulate thymocyte differentiation, promoting the DN3-DN4 transition and the selection of SP thymocytes. As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function. Here, we demonstrate that, in the absence of Inhibins, thymic conventional dendritic cells display reduced levels of MHC Class II (MHCII) and CD86. In addition, the ratio between cTECs and mTECs was affected, indicating that mTEC differentiation was favoured and cTEC diminished in the absence of Inhibins. These changes appeared to impact thymocyte selection leading to a decreased selection of CD4SP thymocytes and increased generation of natural regulatory T cells. These findings demonstrate that Inhibins tune the T cell selection process by regulating both thymocyte and stromal cell differentiation.

No MeSH data available.


Related in: MedlinePlus