Dissecting and modeling the emergent murine TEC compartment during ontogeny

Brunk, Fabian; Michel, Chloé; Holland‐Letz, Tim; Slynko, Alla; Kopp‐Schneider, Annette; Kyewski, Bruno

doi:10.1002/eji.201747006

Cited by 10 publications

(13 citation statements)

References 29 publications

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“…with 2 mg of EdU for 12 d. At 4 h and days 1, 3, 6, 9, and 12, mice were sacrificed and mTEC subsets were analyzed for EdU incorporation. As previously reported, MHCII hi mTECs proliferated at a higher rate than did MHCII lo mTECs (8,43). When MHCII hi mTECs were further separated on the basis of TPA expression, the TPA lo initially preceded the TPA hi ones.…”

Section: Ontogeny and Turnover Of Tpa-defined Mtec Subsetssupporting

confidence: 78%

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Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation

Michel

Miller

Küchler

et al. 2017

The Journal of Immunology

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The basic two-step terminal differentiation model of the medullary thymic epithelial cell (mTEC) lineage from immature MHC class II (MHCII) to mature MHCII mTECs has recently been extended to include a third stage, namely the post-Aire MHCII subset as identified by lineage-tracing models. However, a suitable surface marker distinguishing the phenotypically overlapping pre- from the post-Aire MHCII stage has been lacking. In this study, we introduce the lectin agglutinin (TPA) as a novel cell surface marker that allows for such delineation. Based on our data, we derived the following sequence of mTEC differentiation: TPAMHCII → TPAMHCII → TPAMHCII → TPAMHCII Surprisingly, in the steady-state postnatal thymus TPAMHCII pre-Aire rather than terminally differentiated post-Aire TPAMHCII mTECs were marked for apoptosis at an exceptionally high rate of ∼70%. Hence, only the minor cycling fraction of the MHCII subset (<20%) potentially qualified as mTEC precursors. FoxN1 expression inversely correlated with the fraction of slow cycling and apoptotic cells within the four TPA subsets. TPA also further subdivided human mTECs, although with different subset distribution. Our revised road map emphazises close parallels of terminal mTEC development with that of skin, undergoing an alternative route of cell death, namely cornification rather than apoptosis. The high rate of apoptosis in pre-Aire MHCII mTECs points to a "quality control" step during early mTEC differentiation.

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Section: Ontogeny and Turnover Of Tpa-defined Mtec Subsetssupporting

confidence: 78%

“…4A). The first Aire + mTECs appeared around E14.5 (16,43). The TPA hi subsets also first emerged at E14.5 and ex-panded around E15.5-16.5, and the TPA hi MHCII hi clearly preceded the TPA hi MHCII lo subset.…”

Section: Ontogeny and Turnover Of Tpa-defined Mtec Subsetsmentioning

confidence: 94%

Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation

Michel

Miller

Küchler

et al. 2017

The Journal of Immunology

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“…cTECs are largely MHC II hi between E15.5 and about a week after birth, whereas they are mostly MHC II lo in the adult thymus ( Figure 1b). 31 Therefore, the preponderance of MHC II hi cTECs in the Il7r −/− thymus suggests a partial block in the cTEC MHC II hi to mTEC MHC II hi developmental transition.…”

Section: Resultsmentioning

confidence: 98%

A key role for IL‐7R in the generation of microenvironments required for thymic dendritic cells

Moore

Trotman-Grant

et al. 2017

Immunol Cell Biol

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Interleukin-7 receptor (IL-7R) signaling is critical for multiple stages of T-cell development, but a role in the establishment of the mature thymic architecture needed for T-cell development and thymocyte selection has not been established. Crosstalk signals between developing thymocytes and thymic epithelial cell (TEC) precursors are critical for their differentiation into cortical TECs (cTECs) and medullary TECs (mTECs). Additionally, mTECs-derived factors have been implicated in the recruitment of thymic dendritic cells (DCs) and intrathymic DC development. We therefore examined corticomedullary structure and DC populations in the thymus of Il7r−/− mice. Analysis of TEC phenotype and spatial organization revealed a striking shift in the mTEC to cTEC ratio, accompanied by disorganized corticomedullary structure. Several of the thymic subsets known to have DC potential were nearly absent, accompanied by reductions in DC cell numbers. We also examined chemokine expression in the Il7r−/− thymus, and found a significant decrease in mTEC-derived CCR7 ligand expression, and high levels of cTEC-derived chemokines, including CCL25 and CXCL12. Although splenic DCs were similarly affected, bone marrow precursors capable of giving rise to DCs were unperturbed. Finally, bone marrow chimeras showed that there was no intrinsic need for IL-7R signaling in the development or recruitment of thymic DCs, but that the provision of WT progenitors enhanced reconstitution of thymic DCs from Il7r−/− progenitors. Our results are therefore supportive of a model in which Il7r-dependent cells are required to set up the microenvironments that allow accumulation of thymic DCs.

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“…Among the cells that compose the thymus stroma, such as DCs, macrophages, fibroblasts, B cells and others, TECs are the major component. They are located in both the cortex (cTECs) and medulla (mTECs) of the thymic lobules and have distinct phenotypes, secretomes and roles in thymocyte maturation and selection processes . TECs produce components of the thymus microenvironment, such as insoluble extracellular matrix (ECM) molecules and soluble components like interleukins, growth factors and chemokines that mediate ECM–cell and cell–cell interactions, respectively …”

Section: T‐cell Differentiation Negative Selection and Central Tolermentioning

confidence: 99%

“…They are located in both the cortex (cTECs) and medulla (mTECs) of the thymic lobules and have distinct phenotypes, secretomes and roles in thymocyte maturation and selection processes. 64,65 TECs produce components of the thymus microenvironment, such as insoluble extracellular matrix (ECM) molecules and soluble components like interleukins, growth factors and chemokines that mediate ECM-cell and cell-cell interactions, respectively. 66 In the immune system, particularly in the thymus, cell-cell interactions are importantly mediated by T-cell receptor (TCR)/peptide-MHC signalling, which, in combination with various other stimuli, define cell activation, proliferation and survival.…”

Section: T-cell Differentiation Negative Selection and Central Tolermentioning

confidence: 99%

Update on Aire and thymic negative selection

et al. 2017

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SummaryTwenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological -i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases.

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Dissecting and modeling the emergent murine TEC compartment during ontogeny

Cited by 10 publications

References 29 publications

Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation

Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation

A key role for IL‐7R in the generation of microenvironments required for thymic dendritic cells

Update on Aire and thymic negative selection

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