Endothelial cells act as gatekeepers for LTβR-dependent thymocyte emigration

James, Kieran D.; Cosway, Emilie J.; Lucas, Beth; White, Andrea J.; Parnell, Sonia M.; Carvalho-Gaspar, Manuela; Tumanov, Alexei V.; Anderson, Graham; Jenkinson, William E.

doi:10.1084/jem.20181345

Cited by 24 publications

(34 citation statements)

References 34 publications

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“…Importantly, in LTβR TEC mice, selective intrathymic targeting of LTβR deletion to TEC with Foxn1 Cre directly demonstrates that loss of iNKT cells in these mice is due to defective intrathymic development. Moreover, unaltered thymus emigration in LTβR TEC mice 49 also argues against an impact on iNKT cells caused by defects in this process. Thus, our data indicate that TEC expression of LTβR influences intrathymic development of NKT cells in the thymus, and that this then causes iNKT cell defects in the periphery.…”

Section: Discussionmentioning

confidence: 99%

Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells

et al. 2020

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The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEC low subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104 + CCL21 + mTEC low that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.

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Section: Discussionmentioning

confidence: 99%

Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells

et al. 2020

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“…For instance, the localization of TPEC at the CMJ would make them an attractive candidate to regulate T-cell egress via these mechanisms. Perhaps in line with this, in the LTβR Endo mouse model which have a T-cell progenitor homing defect, there is also clear indication that thymic egress is also LTβR-endothelial dependent ( 49 ). Thus, LTβR Endo mice exhibit an intrathymic accumulation of mature thymocytes at a similar magnitude as seen in the germline LTβR-deficient mouse thymus ( 48 , 51 ).…”

Section: Thymic Endotheliummentioning

confidence: 83%

“…Thymic portal endothelial cells (TPEC) were identified as Ly6C − P-selectin + and were found to be enriched in vessels at the CMJ, with ~60% of CD31 + vessels at the CMJ found to contain TPEC ( 73 ). Importantly, TPEC are selectively reduced in mice lacking LTβR either in all cells, or in models were LTβR is deleted specifically on endothelial cells using a endothelial-specific Cre mouse model (Tie2 Cre ) crossed with LTβR Flox mice, to generate LTβR Endo mice ( 49 , 73 ). Loss of TPEC in these mice is accompanied with a significant reduction in the number of early T-cell progenitors (ETP) within the thymus, indicating a T-cell progenitor homing/colonization defect ( 73 , 74 ).…”

Section: Thymic Endotheliummentioning

confidence: 99%

Non-Epithelial Stromal Cells in Thymus Development and Function

2021

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The thymus supports T-cell development via specialized microenvironments that ensure a diverse, functional and self-tolerant T-cell population. These microenvironments are classically defined as distinct cortex and medulla regions that each contain specialized subsets of stromal cells. Extensive research on thymic epithelial cells (TEC) within the cortex and medulla has defined their essential roles during T-cell development. Significantly, there are additional non-epithelial stromal cells (NES) that exist alongside TEC within thymic microenvironments, including multiple subsets of mesenchymal and endothelial cells. In contrast to our current understanding of TEC biology, the developmental origins, lineage relationships, and functional properties, of NES remain poorly understood. However, experimental evidence suggests these cells are important for thymus function by either directly influencing T-cell development, or by indirectly regulating TEC development and/or function. Here, we focus attention on the contribution of NES to thymic microenvironments, including their phenotypic identification and functional classification, and explore their impact on thymus function.

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“…LTβR-dependent, mFb-associated genes such as extracellular matrixes or proteases might play various roles in organizing the cellularity and function of mTECs. LTβR signal also controls the expression of cell adhesion molecules ICAM-1 and VCAM-1 in mFbs, suggesting the role of mFbs in regulating immune cell trafficking in the thymus ( 72 , 94 ).…”

Section: Medullary Fibroblastsmentioning

confidence: 99%

“…It has been shown that pericytes are responsible for the production of the S1P that promotes thymocyte egress ( 116 ). The trans-endothelial entry of ETPs and exit of mature T cells are regulated by the LTβR expressed in endothelial cells and pericytes ( 94 , 117 ). Although the cellular source of LTβR ligands in the context of controlling cell traffic and the significance of this regulatory mechanism are not yet known, the LTβR may be a potential target to efficiently restore T cell production capacity in certain therapeutic situations such as bone marrow transplantation ( 117 ).…”

Section: The Thymic Vasculature and Blood–thymus Barriermentioning

confidence: 99%

Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development

Nitta

Takayanagi

2021

Front. Immunol.

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The stromal microenvironment in the thymus is essential for generating a functional T cell repertoire. Thymic epithelial cells (TECs) are numerically and phenotypically one of the most prominent stromal cell types in the thymus, and have been recognized as one of most unusual cell types in the body by virtue of their unique functions in the course of the positive and negative selection of developing T cells. In addition to TECs, there are other stromal cell types of mesenchymal origin, such as fibroblasts and endothelial cells. These mesenchymal stromal cells are not only components of the parenchymal and vascular architecture, but also have a pivotal role in controlling TEC development, although their functions have been less extensively explored than TECs. Here, we review both the historical studies on and recent advances in our understanding of the contribution of such non-TEC stromal cells to thymic organogenesis and T cell development. In particular, we highlight the recently discovered functional effect of thymic fibroblasts on T cell repertoire selection.

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Endothelial cells act as gatekeepers for LTβR-dependent thymocyte emigration

Abstract: Thymic emigration is essential for establishing T cell immunity. We show the requirement for LTβR segregates from its control of medullary epithelium. Instead, our study demonstrates LTβR expression by the endothelium acts to rate limit thymocyte egress via perivascular routes.

Cited by 24 publications

References 34 publications

Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells

Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells

Non-Epithelial Stromal Cells in Thymus Development and Function

Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development

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