Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus

Ribeiro, Ana R.; Meireles, Catarina; Rodrigues, Pedro M.; Alves, Nuno L.

doi:10.1002/eji.201444585

Cited by 33 publications

(47 citation statements)

References 25 publications

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“…These results agree with previous reports showing that thymocyte-derived signals are necessary for the late maturation of cTECs [4][5][6]. Ribeiro et al [18] also show that CCRL1 + UEA1 -CD80 -cTECs isolated from E15.5 fetal thymus give rise to UEA1 + CD80 + mTECs, when cultured in the presence of RANK and CD40 stimulation in RTOCs, suggesting Figure 1. Development and heterogeneity of cTECs and mTECs.…”

supporting

confidence: 92%

“…The new paper by Ribeiro et al [18] in this issue of the European Journal of Immunology initially provides further support regarding this developmental stage of pTECs that express cTEC-associated molecules. To do so, Ribeiro et al [18] analyze the expression of the atypical chemokine receptor CCRL1 during mouse ontogeny.…”

Section: Cortical Thymic Epithelial Cells (Ctecs) and Medullary Thymimentioning

confidence: 87%

“…Collectively, the three independent reports [14-16] revealed a new stage in the TEC developmental pathways, i.e. bipotent pTECs progress through a stage in which pTECs display molecular signatures associated with cTECs, before then diversifying into mTECs [11].The new paper by Ribeiro et al [18] in this issue of the European Journal of Immunology initially provides further support regarding this developmental stage of pTECs that express cTEC-associated molecules. To do so, Ribeiro et al [18] analyze the expression of the atypical chemokine receptor CCRL1 during mouse ontogeny.…”

mentioning

confidence: 88%

“…Development and heterogeneity of cTECs and mTECs. pTECs progress through a stage in which they express cTEC-associated molecules (cpTECs; cTEC-like progenitor TECs), including CCRL1 CD205, β5t, and high levels of IL7, before diversifying into mTECs [11,[14][15][16][17][18]. Signals provided by developing thymocytes regulate the development of CCRL1 high CD205 + β5t + IL7 high cTECs.…”

mentioning

confidence: 99%

“…Thus, CCRL1 is important for optimal thymus homeostasis and normal thymocyte development. To analyze the expression of CCRL1 in TECs during embryogenesis, Ribeiro et al [18] use CCRL1-EGFP-knockin mice, in which EGFP is expressed under the control of CCRL1 gene expression [20]. By crossing CCRL1-EGFPknockin mice with IL-7-YFP-transgenic mice, and by flow cytometry analysis of embryonic TECs, the authors show that CCRL1 expression progressively increases during fetal cTEC development.…”

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confidence: 99%

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CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

Ohigashi

Takahama

2014

Eur J Immunol

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Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs),The shaping of T-cell repertoire that is immunocompetent (i.e. useful for self-defense) and self-tolerant (i.e. harmless to the body) is crucial for the development and maintenance of the immune system. Thymic epithelial cells (TECs), which are the major component of the thymic microenvironments, are essential for the generation and repertoire formation of T cells. The thymic cortex, which induces early T-cell development and the positive selection of functionally competent T cells, is characterized by a subset of TECs termed cortical thymic epithelial cells (cTECs), whereas the thymic medulla, which establishes self-tolerance in T cells by the negative selection of self-reactive T cells and the generation of regulatory T cells, is formed by another subset of TECs termed medullary thymic epithelial cells (mTECs). TECs are derived from the endodermal epithelium of the third pharyngeal pouch, and the transcription factor Foxn1 is required Correspondence: Prof. Yousuke Takahama e-mail: takahama@genome.tokushima-u.ac.jp for their generation [1]. The early TECs generated during embryogenesis contain bipotent progenitor thymic epithelial cells (pTECs) that are capable of generating both cTECs and mTECs [2,3]. It is acknowledged that thymocyte development differentially affects cTEC development [4][5][6] and mTEC development [7,8]. However, how pTECs branch into cTECs and mTECs and what regulates their developmental pathways are not fully understood.Several molecular markers that characterize cTECs and mTECs have been identified. For example, cTECs predominantly express keratin 8 (K8), CD205 (DEC205), and CD249 (Ly51), whereas mTECs highly express keratin 5 (K5), CD80, and molecules that bind to the lectin Ulex europaeus agglutinin 1 (UEA1) [9][10][11]. In addition, mTECs, including immature mTECs, strongly express the tight junction molecules claudin-3 and claudin-4 [12]. Molecules that define pTECs are less well known, although it was suggested that pTECs express Plet1 (MTS24) and doubly express K5 and K8 [9,13]. cTECs and mTECs have further been characterized by their expression of functional molecules. DLL4 and IL-7, whichwww.eji-journal.eu Eur. J. Immunol. 2014. 44: 2872-2875 HIGHLIGHTS 2873are important for the induction of early T-cell development, as well as the thymoproteasome subunit β5t and the serine proteasome Prss16, which are critical for the positive selection of developing thymocytes, are highly expressed by cTECs rather than mTECs [10,11]. The cytokine receptor RANK and the nuclear protein Aire, which are pivotal for mTEC development and function in establishing self-tolerance in T cells, are predominantly detectable in mTECs rather than cTECs [10,11]. Chemokines, which essentially regulate the migration of developing thymocytes, are also unequally expressed between cTECs and mTECs; CCL25 and CXCL12 are more abundant in cTECs than mTECs, whereas CCL19, CCL21, and XCL1 are more highly detectable in mTECs than cTECs [...

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supporting

confidence: 92%

Section: Cortical Thymic Epithelial Cells (Ctecs) and Medullary Thymimentioning

confidence: 87%

mentioning

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

Ohigashi

Takahama

2014

Eur J Immunol

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Atypical chemokine receptor 4 (ACKR4/CCX‐CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research

Naser,

Hamza,

Alhili

et al. 2024

Cell Biochemistry & Function

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Atypical chemokine receptor 4 (ACKR4), also known as CCX‐CKR, is a member of the chemokine receptor family that lacks typical G protein signaling activity. Instead, ACKR4 functions as a scavenger receptor that can bind and internalize a wide range of chemokines, influencing their availability and activity in the body. ACKR4 is involved in various physiological processes, such as immune cell trafficking and the development of thymus, spleen, and lymph nodes. Moreover, ACKR4 has been implicated in several pathological conditions, including cancer, heart and lung diseases. In cancer, ACKR4 plays a complex role, acting as a tumor suppressor or promoter depending on the type of cancer and the stage of the disease. For instance, ACKR4 may inhibit the growth and metastasis of breast cancer, but it may also promote the progression of hepatocellular carcinoma and gastric cancer. In inflammatory situations, ACKR4 has been found to modulate the recruitment and activation of immune cells, contributing to the pathogenesis of diseases such as myocardial infraction and pulmonary sarcoidosis. The study of ACKR4 is still ongoing, and further research is needed to fully understand its role in different physiological and pathological contexts. Nonetheless, ACKR4 represents a promising target for the development of novel therapeutic strategies for various diseases.

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CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice

et al. 2015

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Thymus colonisation and thymocyte positioning are regulated by interactions between CCR7 and CCR9, and their respective ligands, CCL19/CCL21 and CCL25. The ligands of CCR7 and CCR9 also interact with the atypical receptor CCRL1 (also known as ACKR4), which is expressed in the thymus and has recently been reported to play an important role in normal αβT-cell development. Here, we show that CCRL1 is expressed within the thymic cortex, predominantly by MHC-II low CD40 − cortical thymic epithelial cells and at the subcapsular zone by a population of podoplanin + thymic epithelial cells in mice.Interestingly, CCRL1 is also expressed by stromal cells which surround the pericytes of vessels at the corticomedullary junction, the site for progenitor cell entry and mature thymocyte egress from the thymus. We show that CCRL1 suppresses thymocyte progenitor entry into the thymus, however, the thymus size and cellularity are the same in adult WT and CCRL1 −/− mice. Moreover, CCRL1 −/− mice have no major perturbations in T-cell populations at different stages of thymic differentiation and development, and have a similar rate of thymocyte migration into the blood. Collectively, our findings argue against a major role for CCRL1 in normal thymus development and function.Keywords: ACKR4 r CCRL1 r Chemokines r T-cell development r Thymic epithelial cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site

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Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus

Cited by 33 publications

References 25 publications

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

Atypical chemokine receptor 4 (ACKR4/CCX‐CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research

CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice

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