Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”

Alves, Nuno L.; Huntington, Nicholas D.; Rodewald, Hans Reimer; Santo, James P. Di

doi:10.1016/j.it.2009.07.010

Cited by 53 publications

(53 citation statements)

References 61 publications

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“…Nevertheless, exogenous administration of hIL-7 [5] or hIL-15 (this report) can independently improve human thymopoiesis indicating human cytokines are more efficient. Multiple factors are important for the commitment (DLL4), survival and division (IL-7, IL-15, stem cell factor), migration (CXCL12 and CCL25) and selection (MHCpeptide) of developing thymocytes [7]. Whether substitution (replacement) of the corresponding human factors will improve human thymopoiesis in HIS mice will require further study.…”

Section: Discussionmentioning

confidence: 99%

“…The recent advances in the development of HIS mice provide a new model to experimentally dissect human lymphocyte biology that may eventually allow us to bridge the knowledge gap between murine and human in vivo studies of immune responses. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…On the other hand, interaction of haematopoietic precursors with murine thymic epithelial cell (TEC) ligands or soluble factors during thymopoiesis and subsequent selection of T cells on murine major histocompatibility complexes (MHC) may generate suboptimal signals for T-cell maintenance. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection.…”

Section: Introductionmentioning

confidence: 99%

“…The generation of these two functionally competent TEC compartments is a prerequisite for normal thymopoiesis. TEC maturation requires reciprocal signals from thymocytes, a symbiotic bi-directional relationship known as ''thymic cross-talk'' [7,10,11].T-cell homeostasis comprises T-cell generation in the thymus, export to the periphery, maintenance of the peripheral naïve T-cell pool and regulation of activated effectors and memory T-cell compartments [12]. Human T-cell development within the thymus has been extensively characterized and critical stages can be defined by sequential expression of cell-surface antigens on differentiating thymocytes.…”

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confidence: 99%

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Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

et al. 2011

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PortugalHuman Immune System (HIS) mice represent a novel biotechnology platform to dissect human haematopoiesis and immune responses. However, the limited human T-cell development that is observed in HIS mice restricts its utility for these applications. Here, we address whether reduced thymopoiesis in HIS mice reflects an autonomous defect in T-cell precursors and/or a defect in the murine thymic niche. Human thymocyte precursors seed the mouse thymus and their reciprocal interactions with murine thymic epithelial cells (TECs) led to both T-cell and TEC maturation. The human thymocyte subsets observed in HIS mice demonstrated survival, proliferative and phenotypic characteristics of their normal human counterparts, suggesting that the intrinsic developmental program of human thymocytes unfolds normally in this xenograft setting. We observed that exogenous administration of human IL-15/IL-15Ra agonistic complexes induced the survival, proliferation and absolute numbers of immature human thymocyte subsets, without any obvious effect on cell-surface phenotype or TCR Vb usage amongst the newly selected mature singlepositive (SP) thymocytes. Finally, when IL-15 was administered early after stem cell transplantation, we noted accelerated thymopoiesis resulting in the more rapid appearance of peripheral naïve T cells. Our results highlight the functional capacity of murine thymic stroma cells in promoting human thymopoiesis in HIS mice but suggest that the ''cross-talk'' between murine thymic stroma and human haematopoietic precursors may be suboptimal. As IL-15 immunotherapy promotes early thymopoiesis, this novel approach could be used to reduce the period of T-cell immunodeficiency in the post-transplant clinical setting. IntroductionSixty million years of evolution has generated important differences between the murine and human immune systems (HISs). As such, our knowledge of lymphocyte development, homeostasis and immune responses that is largely derived from mouse studies may not be directly applicable to man. The recent advances in the development of HIS mice provide a new model to experimentally dissect human lymphocyte biology that may eventually allow us to bridge the knowledge gap between murine and human in vivo studies of immune responses. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection. TECs are classically divided into two specialized functional subsets, cortical (cTECs) and medullary (mTECs). While cTECs are important at early stages of T-cell development and mediate positive selection, mTECs are critical at later stages governing negative selection and providing survival signals to mature single-positive (SP) thymocytes [6,8,9]. The generation of these two functionally competent TEC compartments is a prerequisite ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

et al. 2011

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DL4‐mediated Notch signaling is required for the development of fetal αβ and γδ T cells

et al. 2013

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T-cell development depends upon interactions between thymocytes and thymic epithelial cells (TECs). The engagement of delta-like 4 (DL4) on TECs by Notch1 expressed by blood-borne BM-derived precursors is essential for T-cell commitment in the adultthymus. In contrast to the adult, the earliest T-cell progenitors in the embryo originate in the fetal liver and migrate to the nonvascularized fetal thymus via chemokine signals. Within the fetal thymus, some T-cell precursors undergo programmed TCRγ and TCRδ rearrangement and selection, giving rise to unique γδ T cells. Despite these fundamental differences between fetal and adult T-cell lymphopoiesis, we show here that DL4-mediated Notch signaling is essential for the development of both αβ and γδ T-cell lineages in the embryo. Deletion of the DL4 gene in fetal TECs results in an early block in αβ T-cell development and a dramatic reduction of all γδ T-cell subsets in the fetal thymus. In contrast to the adult, no dramatic deviation of T-cell precursors to alternative fates was observed in the fetal thymus in the absence of Notch signaling. Taken together, our data reveal a common requirement for DL4-mediated Notch signaling in fetal and adult thymopoiesis.Keywords: Delta-like 4 · Fetal T-cell development · FoxN1Cre · Thymic epithelial cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionT cells differentiate in the thymus following sequential developmental steps that constantly require interaction with thymic epithelial cells (TECs), the major cell type of the thymic stroma. TECs are organized as a 3D network that facilitates thymocyte migration, and provide important thymopoietic factors such as Correspondence: Dr. Isabel Ferrero e-mail: Isabel.Ferrero@unil.ch Kit ligand, FLT3L, IL-7, CCL25, CXCL12, CCL19, and CCL21. Anatomically, the adult thymus is divided into cortex and medulla, each comprised of specialized TECs, cTECs (cortical epithelial cells) and mTECs (medullary epithelial cells), with different phenotype and function [1][2][3]. This epithelial compartmentalization of the adult thymus is essential for the correct development of T cells, and epithelial cells require specific interactions with developing thymocytes in order to maintain the cTEC versus mTEC specification. Such a mutual interdependency between thymocytes and TECs has been called "thymic crosstalk" [4].www.eji-journal.eu 2846 Isabel Ferrero et al. Eur. J. Immunol. 2013. 43: 2845-2853 In the adult, BM-derived common lymphoid precursors continuously seed the thymus from the bloodstream [5]. Inside the thymus, these precursors adopt a T-cell fate through a noncell autonomous process that strictly depends on Notch signaling mediated by interactions with cTECs. Notch signaling directs the lymphoid precursors towards a T-cell lineage differentiation program and blocks alternative lineage differentiation pathways [6][7][8][9].Fetal thymocyte development differs from the adult in two main aspects. First, fetal thymoc...

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Serial progression of cortical and medullary thymic epithelial microenvironments

et al. 2013

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Thymic epithelial cells (TECs) provide key instructive signals for T-cell differentiation. Thymic cortical (cTECs) and medullary (mTECs) epithelial cells constitute two functionally distinct microenvironments for T-cell development, which derive from a common bipotent TEC progenitor. While seminal studies have partially elucidated events downstream of bipotent TECs in relation to the emergence of mTECs and their progenitors, the control and timing of the emergence of the cTEC lineage, particularly in relation to that of mTEC progenitors, has remained elusive. In this review, we describe distinct models that explain cTEC/mTEC lineage divergence from common bipotent progenitors. In particular, we summarize recent studies in mice providing evidence that mTECs, including the auto-immune regulator+ subset, derive from progenitors initially endowed with phenotypic properties typically associated with the cTEC lineage. These observations support a novel “serial progression” model of TEC development, in which progenitors serially acquire cTEC lineage markers, prior to their commitment to the mTEC differentiation pathway. Gaining a better understanding of the phenotypic properties of early stages in TEC progenitor development should help in determining the mechanisms regulating cTEC/mTEC lineage development, and in strategies aimed at thymus reconstitution involving TEC therapy.

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Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”

Cited by 53 publications

References 61 publications

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

DL4‐mediated Notch signaling is required for the development of fetal αβ and γδ T cells

Serial progression of cortical and medullary thymic epithelial microenvironments

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