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

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

doi:10.3389/fimmu.2020.01342

Cited by 12 publications

(10 citation statements)

References 29 publications

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“…Sexual dimorphism in the immune system is well recognized and it is broadly summarized with the concept that women tend to develop more autoimmune diseases than men, while men are more vulnerable to some infectious diseases. Sex hormones, and in particular androgens, heavily influence thymic function primarily through the regulation of TEC differentiation and function ( 121 , 122 ). Studies in murine models demonstrated that age-related thymic dysfunction is faster in males than in females.…”

Section: Manipulating Thymic Function To Enhance Efficacy Of Cancer Immunotherapymentioning

confidence: 99%

“…Most of our mechanistic understanding of the effects of hormones on thymic function is largely restricted to the effects of androgens in male subjects. However, recent studies have started characterizing genders differences in thymic function and in response to SSA ( 122 , 125 ). It has been shown that, in female mice, age induces a higher degree of central tolerance imbalance characterized by the reduction of medullary TECs expressing the autoimmune regulator gene (AIRE), which could contribute to the increased risk of autoimmune disease observed in middle-aged women ( 126 ).…”

Section: Manipulating Thymic Function To Enhance Efficacy Of Cancer Immunotherapymentioning

confidence: 99%

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Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Cardinale¹,

Compagnucci²,

Locatelli³

et al. 2021

Front. Immunol.

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The capacity of T cells to recognize and mount an immune response against tumor antigens depends on the large diversity of the T-cell receptor (TCR) repertoire generated in the thymus during the process of T-cell development. However, this process is dramatically impaired by immunological insults, such as that caused by cytoreductive cancer therapies and infections, and by the physiological decline of thymic function with age. Defective thymic function and a skewed TCR repertoire can have significant clinical consequences. The presence of an adequate pool of T cells capable of recognizing specific tumor antigens is a prerequisite for the success of cancer immunotherapy using checkpoint blockade therapy. However, while this approach has improved the chances of survival of patients with different types of cancer, a large proportion of them do not respond. The limited response rate to checkpoint blockade therapy may be linked to a suboptimal TCR repertoire in cancer patients prior to therapy. Here, we focus on the role of the thymus in shaping the T-cell pool in health and disease, discuss how the TCR repertoire influences patients’ response to checkpoint blockade therapy and highlight approaches able to manipulate thymic function to enhance anti-tumor immunity.

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Section: Manipulating Thymic Function To Enhance Efficacy Of Cancer Immunotherapymentioning

confidence: 99%

Section: Manipulating Thymic Function To Enhance Efficacy Of Cancer Immunotherapymentioning

confidence: 99%

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Cardinale¹,

Compagnucci²,

Locatelli³

et al. 2021

Front. Immunol.

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“…It is the thymic epithelial compartment, therefore, that drives androgen-induced thymic involution. Of note, TEC ARKO thymi were not as large as global ARKO thymi, which may have been due to poor deletion of AR in cortical cTEC (34) or, perhaps, to contributions by another cell type. Androgen signaling in TEC appears to mediate changes in thymus size by inhibiting TEC proliferation (37) and inhibiting TEC expression of molecules that promote thymocyte survival and proliferation, such as Ccl21 and Il7 (33,38).…”

Section: Thymic Involutionmentioning

confidence: 90%

“…Exogenous and endogenous androgens have potent effects on the thymus, with castration or inhibition of androgen synthesis causing dramatic thymic enlargement, and treatment with androgens causing atrophy (17,21,32). This is driven by signaling through the classical AR, since AR-deficient (ARKO) male mice have thymi that are twice the size of wild-type controls (33,34) and are completely refractory to treatment with exogenous androgens (33,35).…”

Section: Thymic Involutionmentioning

confidence: 99%

Effects of sex steroids on thymic epithelium and thymocyte development

Taves

Ashwell

2022

Front. Immunol.

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Sex steroid hormones have major effects on the thymus. Age-related increases in androgens and estrogens and pregnancy-induced increases in progestins all cause dramatic thymic atrophy. Atrophy can also be induced by treatment with exogenous sex steroids and reversed by ablation of endogenous sex steroids. Although these observations are frequently touted as evidence of steroid lymphotoxicity, they are often driven by steroid signaling in thymic epithelial cells (TEC), which are highly steroid responsive. Here, we outline the effects of sex steroids on the thymus and T cell development. We focus on studies that have examined steroid signaling in vivo, aiming to emphasize the actions of endogenous steroids which, via TEC, have remarkable programming effects on the TCR repertoire. Due to the dramatic effects of steroids on TEC, especially thymic involution, the direct effects of sex steroid signaling in thymocytes are less well understood. We outline studies that could be important in addressing these possibilities, and highlight suggestive findings of sex steroid generation within the thymus itself.

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“…We found a pronounced reduction in cTEC/mTEC ratio in males younger than 3 months of age compared to age-matched females, which resulted from a relative lack of cTECs rather than an increased proportion of mTECs. Androgens are known to negatively impact on TEC proliferation and regeneration (52,54), and especially impair cTEC regeneration (54,55), whereas estrogens have a negative effect on mTECs (56).…”

Section: Epcam Pdpn Cd200 and Cd49f Reliably Identify Human Tecs By Flow Cytometrymentioning

confidence: 99%

Novel Combination of Surface Markers for the Reliable and Comprehensive Identification of Human Thymic Epithelial Cells by Flow Cytometry: Quantitation and Transcriptional Characterization of Thymic Stroma in a Pediatric Cohort

et al. 2021

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Thymic epithelial cells (TECs) are essential in supporting the development of mature T cells from hematopoietic progenitor cells and facilitate their lineage-commitment, proliferation, T-cell receptor repertoire selection and maturation. While animal model systems have greatly aided in elucidating the contribution of stromal cells to these intricate processes, human tissue has been more difficult to study, partly due to a lack of suitable surface markers comprehensively defining human TECs. Here, we conducted a flow cytometry based surface marker screen to reliably identify and quantify human TECs and delineate medullary from cortical subsets. These findings were validated by transcriptomic and histologic means. The combination of EpCAM, podoplanin (pdpn), CD49f and CD200 comprehensively identified human TECs and not only allowed their reliable distinction in medullary and cortical subsets but also their detailed quantitation. Transcriptomic profiling of each subset in comparison to fibroblasts and endothelial cells confirmed the identity of the different stromal cell subsets sorted according to the proposed strategy. Our dataset not only demonstrated transcriptional similarities between TEC and cells of mesenchymal origin but furthermore revealed a subset-specific distribution of a specific set of extracellular matrix-related genes in TECs. This indicates that TECs significantly contribute to the distinct compartmentalization – and thus function – of the human thymus. We applied the strategy to quantify TEC subsets in 31 immunologically healthy children, which revealed sex-specific differences of TEC composition early in life. As the distribution of mature CD4- or CD8-single-positive thymocytes was correspondingly altered, the composition of the thymic epithelial compartment may directly impact on the CD4-CD8-lineage choice of thymocytes. We prove that the plain, reliable strategy proposed here to comprehensively identify human TEC subpopulations by flow cytometry based on surface marker expression is suitable to determine their frequency and phenotype in health and disease and allows sorting of live cells for downstream analysis. Its use reaches from a reliable diagnostic tool for thymic biopsies to improved phenotypic characterization of thymic grafts intended for therapeutic use.

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

Cited by 12 publications

References 29 publications

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Effects of sex steroids on thymic epithelium and thymocyte development

Novel Combination of Surface Markers for the Reliable and Comprehensive Identification of Human Thymic Epithelial Cells by Flow Cytometry: Quantitation and Transcriptional Characterization of Thymic Stroma in a Pediatric Cohort

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