Establishment and functioning of intrathymic microenvironments

Anderson, Graham; Jenkinson, William E.; Jones, Terry; Parnell, Sonia M.; Kinsella, Francesca; White, Andrea J.; Pongrácz, Judit E.; Rossi, Simona W.; Jenkinson, Eric J.

doi:10.1111/j.0105-2896.2006.00347.x

Cited by 100 publications

(113 citation statements)

References 182 publications

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“…[6][7][8] Thymus organogenesis and the maintenance of thymus architecture are dependent on lymphostromal cross talk. 9,10 Although thymic epithelial cells (TECs) provide growth factors and signals that will promote migration and T lineage commitment to the developing lymphocytes, the presence of lymphocytes is also necessary for the differentiation and functional maturation of TECs. 11,12 Postnatal disruption of TECs results in thymic atrophy, 13,14 whereas restoration of thymocyte development can reestablish TEC architecture in cases where the defect was thymocyte intrinsic.…”

Section: Introductionmentioning

confidence: 99%

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

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Section: Introductionmentioning

confidence: 99%

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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“…T-cell development in the thymus is dependent on the thymic microenvironment, in which epithelial cells are the major components [1,2]. The importance of thymic epithelial cells (TECs) has been demonstrated in patients and in animals in which genetic mutations or deletions affect thymic epithelial cell development or function.…”

Section: Introductionmentioning

confidence: 99%

Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells

Lai

Jin

2009

Stem Cells

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Thymopoiesisis regulated by the thymic microenvironment, of which epithelial cells are the major components. Both cortical and medullary thymic epithelial cells (TECs) have been shown to arise from a common progenitor cell. Here we show for the first time that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to differentiate into cells that have the phenotype of thymic epithelial progenitors (TEPs). When placed in vivo, these mESC-derived TEPs self-renew, develop into TECs, and reconstitute the normal thymic architecture. Functionally, these ESC-derived TEPs enhanced thymocyte regeneration after bone marrow transplantation and increased the number of functional naive splenic T cells. In addition to providing a model to study the molecular events underlying thymic epithelial cell development, the ability to selectively induce the development of TEPs in vitro from mESCs has important implications regarding the prevention and/or treatment of primary and secondary T-cell immunodeficiencies.

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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%

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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Establishment and functioning of intrathymic microenvironments

Cited by 100 publications

References 182 publications

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells

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

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