Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self

Derbinski, Jens; Schulte, Antje; Kyewski, Bruno; Klein, Ludger

doi:10.1038/ni723

Cited by 940 publications

(906 citation statements)

References 60 publications

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“…In recent years, however, it has been shown that it is expressed in the thymus, along with many other tissue-restricted antigens [3]. AIRE is necessary for the expression of most of these antigens, but the possibility of additional quantitative regulation by factors specific for each antigen needs to be explored.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, it has been clearly demonstrated that the expression of self-antigens, such as insulin, in the medullary thymic epithelial cells (mTECs) is an essential component for central tolerance [1][2][3][4]. Thymocytes entering the thymus after their development in the bone marrow require signals to survive and exit to the periphery to join the properly formed circulating T lymphocytes [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…These signals are both positive and negative, the former requiring functional T cell receptors and the latter triggered by recognition of self-antigens [5,6]. Therefore, it is widely thought that the 'promiscuous' gene expression of self-antigens in the thymus serves the purpose of assessing the responses of newly formed thymocytes to self-antigens [3]. This process is necessary in order to purge the self-reactive cells from the system and avoid autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

“…The expression of self-antigens has been localised to mTECs [2][3][4] and is an essential player in the deletion of self-reactive T cells as well as the generation of T regulatory cells [7][8][9]. Although the expression of self-antigens in the thymic epithelial cells is well documented, not much is known about how their levels are regulated.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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Aims/hypothesis The expression of tissue-specific selfantigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature. Methods Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-γ and cell-tocell contact with thymocytes in co-culture. Results Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-γ, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, coculture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression. Conclusions/interpretation We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulinspecific mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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“…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 for normal thymopoiesis.…”

Section: Introductionmentioning

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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Isolation of Thymic Epithelial Cells and Analysis by Flow Cytometry

Jain

Gray

2014

CP in Immunology

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The epithelial cells of the thymus govern the differentiation of hematopoietic precursors into T cells, which are critical for acquired immunity. Thymic epithelial cells (TEC) provide molecular cues that direct precursor recruitment, commitment to the T cell lineage, thymocyte proliferation, and the processes of positive and negative selection. Despite the importance of TEC to the immune system, fundamental questions regarding their differentiation, turnover, and function throughout life remain unanswered. This knowledge gap is largely due to technical difficulties in isolating, quantifying, and purifying this rare cell type. Here, we describe methods for the enzymatic digestion of the thymus to obtain single-cell suspensions of TEC, their analysis by flow cytometry, enrichment using magnetic beads, and purification for a variety of downstream applications.

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Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self

Cited by 940 publications

References 60 publications

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

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

Isolation of Thymic Epithelial Cells and Analysis by Flow Cytometry

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