Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice.

Anna S Wilhelmson,Alexandra Stubelius,Marta Lantero Rodriguez,Åsa Tivesten,Susanne Lindgren,Hans Carlsten,Johan Bourghardt Fagman,Elin Svedlund Eriksson,Pamela J Fink,Olov Ekwall,Inger Johansson

doi:10.3389/fimmu.2020.01342

Anna S Wilhelmson, Alexandra Stubelius + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2020.01342

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Abstract

Androgens have profound effects on T cell homeostasis, including regulation of thymic T lymphopoiesis (thymopoiesis) and production of recent thymic emigrants (RTEs), i. e., immature T cells that derive from the thymus and continue their maturation to mature naïve T cells in secondary lymphoid organs. Here we investigated the androgen target cell for effects on thymopoiesis and RTEs in spleen and lymph nodes. Male mice with a general androgen receptor knockout (G-ARKO), T cell-specific (T-ARKO), or epithelial cell-specific (E-ARKO) knockout were examined. G-ARKO mice showed increased thymus weight and increased numbers of thymic T cell progenitors. These effects were not T cell-intrinsic, since T-ARKO mice displayed unaltered thymus weight and thymopoiesis. In line with a role for thymic epithelial cells (TECs), E-ARKO mice showed increased thymus weight and numbers of thymic T cell progenitors. Further, E-ARKO mice had more CD4+ and CD8+ T cells in spleen and an increased frequency of RTEs among T cells in spleen and lymph nodes. Depletion of the androgen receptor in epithelial cells was also associated with a small shift in the relative number of cortical (reduced) and medullary (increased) TECs and increased CCL25 staining in the thymic medulla, similar to previous observations in castrated mice. In conclusion, we demonstrate that the thymic epithelium is a target compartment for androgen-mediated regulation of thymopoiesis and consequently the generation of RTEs.

Highlights

Androgens, such as testosterone, are important modulators of the immune system and immunerelated disorders [1]
Despite a highly efficient knockout of androgen receptor (AR) exon 2 genomic DNA (gDNA) in CD3+ T cells (Supplemental Figure 2A), TARKO mice had unchanged thymus weight and cellularity, and the number of T cell precursors were unaffected by ARdeficiency in T cells (Supplemental Figures 2B–G), showing that the enhanced thymopoiesis in AR deficiency is not T cell-intrinsic
We show that epithelial cells are a target for androgen/AR-mediated actions on thymopoiesis, splenic T cells, and Recent thymic emigrants (RTEs) in secondary lymphoid organs

Summary

Introduction

Androgens, such as testosterone, are important modulators of the immune system and immunerelated disorders [1]. Androgens suppress the number of peripheral T cells in both mice and men [2,3,4,5]. It is well recognized that androgens have a crucial impact on thymus size and contribute to the involution of the thymus taking place during puberty in both mice and humans. Recent thymic emigrants (RTEs), i.e., immature T cells that derive from the thymus and continue their maturation to mature naïve T cells in secondary lymphoid organs, are regulated by androgens; the fraction of RTEs increases in the periphery after castration and/or androgen deprivation therapy of both mice and humans [3, 5]. Besides being progenitors to mature T cells, RTEs have distinct properties and may play specific roles in immune disorders [13]

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