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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 expression but not CD11c+ cells is reduced in thymus of Inhα−/− mice. Representative micrographs of thymic sections from 2-week-old Inhα+/+ (n = 3) and Inhα−/− (n = 6) mice stained for MHCII (a) and CD11c (b) are shown at 5x (top panels) and 40x (bottom panels) magnification. (a) MHCII staining and summary of data expressing the percentage of area stained per field (top, P = 0.002) and the MHCII staining intensity (bottom, P = 0.04) are shown. (b) CD11c staining and summary of data expressing the percentage of area stained per field (top) and the CD11c staining intensity (bottom). Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.
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fig1: MHCII expression but not CD11c+ cells is reduced in thymus of Inhα−/− mice. Representative micrographs of thymic sections from 2-week-old Inhα+/+ (n = 3) and Inhα−/− (n = 6) mice stained for MHCII (a) and CD11c (b) are shown at 5x (top panels) and 40x (bottom panels) magnification. (a) MHCII staining and summary of data expressing the percentage of area stained per field (top, P = 0.002) and the MHCII staining intensity (bottom, P = 0.04) are shown. (b) CD11c staining and summary of data expressing the percentage of area stained per field (top) and the CD11c staining intensity (bottom). Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.

Mentions: We have previously demonstrated that Inhα−/− mice have delayed T cell development mainly at the DN to DP transition and reduced thymocyte numbers [25]. As engagement of endogenous peptide-MHCII complexes by the TCRs expressed on developing thymocytes is crucial for their selection and survival [8], we analyzed the expression of MHCII in the thymic stroma of 2-week-old Inhα−/− mice or Inhα+/+. This age was selected to minimize the possible interference of intrinsic factors present in the Inhα−/− mice, since it has been reported that this mouse develops gonadal sex cord-stromal tumors as early as 4 weeks of age which cause cancer related cachexia-like symptoms [3, 28]. Immunohistochemical analysis showed that thymi of Inhα−/− mice expressed reduced levels of MHCII molecules, which was evident in the thymic medulla (Figure 1(a)). Although cTECs express both MHCI and MHCII molecules, the levels of MHCII staining in the cortex are lower than in the medulla, possibly due to thymocyte masking of MHCII as a result of the smaller proportion of cTECs/thymocytes in the cortex [29]. Therefore, by this technique we cannot rule out the possibility that cortical stromal cells could also show alterations in their MHCII expression.


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 expression but not CD11c+ cells is reduced in thymus of Inhα−/− mice. Representative micrographs of thymic sections from 2-week-old Inhα+/+ (n = 3) and Inhα−/− (n = 6) mice stained for MHCII (a) and CD11c (b) are shown at 5x (top panels) and 40x (bottom panels) magnification. (a) MHCII staining and summary of data expressing the percentage of area stained per field (top, P = 0.002) and the MHCII staining intensity (bottom, P = 0.04) are shown. (b) CD11c staining and summary of data expressing the percentage of area stained per field (top) and the CD11c staining intensity (bottom). Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4418002&req=5

fig1: MHCII expression but not CD11c+ cells is reduced in thymus of Inhα−/− mice. Representative micrographs of thymic sections from 2-week-old Inhα+/+ (n = 3) and Inhα−/− (n = 6) mice stained for MHCII (a) and CD11c (b) are shown at 5x (top panels) and 40x (bottom panels) magnification. (a) MHCII staining and summary of data expressing the percentage of area stained per field (top, P = 0.002) and the MHCII staining intensity (bottom, P = 0.04) are shown. (b) CD11c staining and summary of data expressing the percentage of area stained per field (top) and the CD11c staining intensity (bottom). Values are expressed as mean ± SEM. Statistical significance: ∗P ≤ 0.05.
Mentions: We have previously demonstrated that Inhα−/− mice have delayed T cell development mainly at the DN to DP transition and reduced thymocyte numbers [25]. As engagement of endogenous peptide-MHCII complexes by the TCRs expressed on developing thymocytes is crucial for their selection and survival [8], we analyzed the expression of MHCII in the thymic stroma of 2-week-old Inhα−/− mice or Inhα+/+. This age was selected to minimize the possible interference of intrinsic factors present in the Inhα−/− mice, since it has been reported that this mouse develops gonadal sex cord-stromal tumors as early as 4 weeks of age which cause cancer related cachexia-like symptoms [3, 28]. Immunohistochemical analysis showed that thymi of Inhα−/− mice expressed reduced levels of MHCII molecules, which was evident in the thymic medulla (Figure 1(a)). Although cTECs express both MHCI and MHCII molecules, the levels of MHCII staining in the cortex are lower than in the medulla, possibly due to thymocyte masking of MHCII as a result of the smaller proportion of cTECs/thymocytes in the cortex [29]. Therefore, by this technique we cannot rule out the possibility that cortical stromal cells could also show alterations in their MHCII expression.

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