The Ins and Outs of Thymic Epithelial Cell Differentiation and Function

Matsumoto, Minoru; Rodrigues, Pedro M.; Sousa, Laura; Tsuneyama, Koichi; Alves, Nuno L.

doi:10.1007/978-3-030-12040-5_3

Cited by 7 publications

(7 citation statements)

References 192 publications

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“…The immune deficits that occur during aging in all vertebrates 1 have been related with profound alterations in the thymus, 2‐8 particularly in its epithelial microenvironment, 9‐11 which maintains a crosstalk with the developing thymocytes. Nevertheless, other studies have proposed that the main factor governing thymic involution is the loss of pro‐T cells and that the thymic epithelium is neither necessary nor sufficient for thymic aging 12 …”

Section: Introductionmentioning

confidence: 99%

Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development

García‐Ceca

Montero-Herradón

Zapata

2020

Developmental Dynamics

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Background: The epithelial microenvironment is involved in thymus aging, but the possible role of EphB receptors that govern the thymic epithelium development has not been investigated. Herein, we study the changes undergone by the thymus of EphB-deficient mice throughout their life. Results: Immune alterations occurring throughout life were more severe in mutant than in wild-type (WT) mice. Mutant thymuses exhibit lower cellularity than WT ones, as well as lower proportions of early thymic progenitors cells and double-positive (CD4 + CD8 +) thymocytes, but higher of double-negative (CD4 − CD8 −) and single-positive (CD4 + CD8 − , CD4 − CD8 +) cells. Throughout life, CD4 + naïve cells decreased particularly in mutant mice. In correlation, memory T cells, largely CD8 + cells, increased. Aged thymic epithelium undergoes changes including appearance of big epithelial free areas, decrease of K8 + K5 − areas, which, however, contain higher proportions of Ly51 + UEA1 − cortical epithelial cells, in correlation with reduced Aire + medullary epithelial cells. Also, aged thymuses particularly those derived from mutant mice exhibited increased collagen IV, fat-storing cells, and connective cells. Conclusions: The absence of EphB accelerates the alterations undergone throughout life by both thymic epithelium and thymocytes, and the proportions of peripheral naïve and memory T cells, all of which are hallmarks of immune aging.

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Section: Introductionmentioning

confidence: 99%

Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development

García‐Ceca

Montero-Herradón

Zapata

2020

Developmental Dynamics

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“…Noteworthy, the expression of CD80 was increased in AIRE -/- spheroids (1.57% in AIRE WT to 37.7% in AIRE -/- ) and the expression of MHC-II molecules did not change in both preparations. Three major stages can be observed along mTEC maturation: i) the immature mTEC presents MHC-II low , CD80 low and Aire low , ii) during TRAs, mTECs exhibit their mature stage, presenting MHC-II high , CD80 high and Aire high , and iii) at the post-Aire stage, mTECs are MHC intermediary , CD80 intermediary , accompanied by an increased rate of apoptotic cells [2]. As observed in Figure 4 A/B, the AIRE WT spheroids presents features of an immature mTEC constitutively exhibiting low expression of AIRE, as previously reported by our group [17].…”

Section: Discussionmentioning

confidence: 99%

“…The cortex is mainly formed by cortical thymic epithelial cells (cTECs), and the medulla is primarily formed by medullary thymic epithelial cells (mTECs), which in mice present the CD45 - , EpCam + , Ly51 + , UEA1 + phenotype [1-3]. Other cell types include thymic seeding progenitors, thymocytes at different stages of maturation, including double-negative (CD4 - CD8 - ), double-positive (CD4 + CD8 + ), and single-positive (CD4 + CD8 - and CD4 - CD8 + ) thymocytes, thymic B cells, macrophages, dendritic cells, and Hassall’s corpuscles [2].…”

Section: Introductionmentioning

confidence: 99%

The absence of the autoimmune regulator gene (AIRE) impairs the three-dimensional structure of medullary thymic epithelial cell spheroids

Monteleone-Cassiano

Dernowsek

Mascarenhas

et al. 2021

Preprint

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Besides controlling the expression of peripheral tissue antigens, the autoimmune regulator (AIRE) gene also regulates the expression of adhesion genes in medullary thymic epithelial cells (mTECs), an essential process for mTEC-thymocyte interaction for triggering the negative selection in the thymus. For these processes to occur, it is necessary that the medulla compartment forms an adequate three-dimensional (3D) architecture, preserving the thymic medulla. Previous studies have shown that AIRE knockout (KO) mice have a small and disorganized thymic medulla; however, whether Aire influences the mTEC-mTEC interaction in the maintenance of the 3D structure has been little explored. Considering that AIRE controls cell adhesion genes, we hypothesized that this gene affects 3D mTEC-mTEC interaction. To test this, we constructed an in vitro model system for mTEC spheroid formation, in which cells adhere to each other, establishing a 3D structure. The effect of Aire on mTEC-mTEC adhesion was evaluated by comparing AIRE wild type (AIREWT) versus Aire KO (AIRE-/-) mTECs. Considering the 3D spheroid model evaluated, we reported that the absence of AIRE disorganizes the 3D structure of mTEC spheroids, promotes a differential regulation of mTEC classical surface markers, and modulates genes encoding adhesion and other molecules.

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“…The intricate 3D network allows close proximity between the developing LPCs and TECs. TECs exhibit different morphology and gene expression profiles, and provide migratory cues (through the expression of several chemokines) to LPCs' homing, as well as to the migration of the developing lymphoblasts across the distinct thymic compartments (reviewed in [10][11][12][13][14][15]). TECs subsets also provide distinct microenvironmental niches and signals essential for proper thymocyte differentiation (reviewed in [11,13,16,17]).…”

Section: Thymus Compositionmentioning

confidence: 99%

Thymus Inception: Molecular Network in the Early Stages of Thymus Organogenesis

Figueiredo

Zilhão

Neves

2020

IJMS

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The thymus generates central immune tolerance by producing self-restricted and self-tolerant T-cells as a result of interactions between the developing thymocytes and the stromal microenvironment, mainly formed by the thymic epithelial cells. The thymic epithelium derives from the endoderm of the pharyngeal pouches, embryonic structures that rely on environmental cues from the surrounding mesenchyme for its development. Here, we review the most recent advances in our understanding of the molecular mechanisms involved in early thymic organogenesis at stages preceding the expression of the transcription factor Foxn1, the early marker of thymic epithelial cells identity. Foxn1-independent developmental stages, such as the specification of the pharyngeal endoderm, patterning of the pouches, and thymus fate commitment are discussed, with a special focus on epithelial–mesenchymal interactions.

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The Ins and Outs of Thymic Epithelial Cell Differentiation and Function

Cited by 7 publications

References 192 publications

Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development

Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development

The absence of the autoimmune regulator gene (AIRE) impairs the three-dimensional structure of medullary thymic epithelial cell spheroids

Thymus Inception: Molecular Network in the Early Stages of Thymus Organogenesis

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