Inhibins Tune the Thymocyte Selection Process by Regulating Thymic Stromal Cell Differentiation

Ebzadrel Carbajal-Franco,Eduardo A García-Zepeda,Germán R Alemán-Muench,Marisol De La Fuente-Granada,Gloria Soldevila

doi:10.1155/2015/837859

Ebzadrel Carbajal-Franco, Eduardo A García-Zepeda + Show 3 more

Open Access

https://doi.org/10.1155/2015/837859

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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.

Highlights

Inhibins are members of the TGF-β superfamily that regulate different cellular functions including proliferation, apoptosis, and differentiation of several cell types and play a role in the immune system.Activins and Inhibins were first described as hormones that regulate FSH release by the pituitary, either activating or inhibiting its release, respectively
As engagement of endogenous peptide-Major Histocompatibility Complex (MHC) Class II (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+/+
Immunohistochemical analysis showed that thymi of Inhα−/− mice expressed reduced levels of MHCII molecules, which was evident in the thymic medulla (Figure 1(a))

Summary

Introduction

Inhibins are members of the TGF-β superfamily that regulate different cellular functions including proliferation, apoptosis, and differentiation of several cell types and play a role in the immune system (reviewed in [1]).Activins and Inhibins were first described as hormones that regulate FSH release by the pituitary, either activating or inhibiting its release, respectively. Our results indicated that there was a slight decrease, not significant, in CD11c+ cells in Inhα−/− thymi compared to Inhα+/+ (Figure 1(b)), suggesting that the difference in MHCII could not merely be attributed to DCs. 3.2.

Results

Conclusion