Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

@article{Hinterberger2010AutonomousRO,
  title={Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance},
  author={Maria Hinterberger and Martin Aichinger and Olivia Prazeres da Costa and David Voehringer and Reinhard W. Hoffmann and Ludger Klein},
  journal={Nature Immunology},
  year={2010},
  volume={11},
  pages={512-519}
}
Medullary thymic epithelial cells (mTECs) serve an essential function in central tolerance by expressing peripheral-tissue antigens. These antigens may be transferred to and presented by dendritic cells (DCs). Therefore, it is unclear whether mTECs, in addition to being an antigen reservoir, also serve a mandatory function as antigen-presenting cells. Here we diminished major histocompatibility complex (MHC) class II on mTECs through transgenic expression of a 'designer' microRNA specific for… 
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247 Citations
Highly Influential Citations
12
Background Citations
102
Methods Citations
7
Results Citations
9

247 Citations

Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction.
Differential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates
TLDR
It is suggested, using new transgenic mouse lines and single cell transcriptome analyses, that specific mTEC subsets are associated with distinct T cell fates, and may have a function in directing distinct mechanisms of T cell tolerance.
The role of the thymic medulla in T cell development and tolerance induction
TLDR
Using a novel approach based on chemokine receptor expression, stages in the positive selection process are mapped, and a model to study αβT cell development in the absence of medullary thymic epithelial cells (mTEC) is developed, highlighting differences in the developmental requirements of conventional and regulatory CD4+ T cells.
The Role of Dendritic Cells in Central Tolerance
TLDR
The literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation are reviewed, and its potential mechanisms and future directions are discussed.
Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus.
Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance.
Lymphotoxin Signals from Positively Selected Thymocytes Regulate the Terminal Differentiation of Medullary Thymic Epithelial Cells
TLDR
This study analyzes late-stage mTEC development in mouse thymus in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall’s corpuscles, and shows that Aire expression and terminal differentiation within the mT EC lineage are temporally separable events that are controlled by distinct mechanisms.
Analysis of APC Types Involved in CD4 Tolerance and Regulatory T Cell Generation Using Reaggregated Thymic Organ Cultures
TLDR
The data indicate that thymic epithelium alone is capable of promoting self-tolerance by eliminating autoreactive CD4 single-positive thymocytes and by supporting regulatory T cell (Treg) development.
Thymic and peripheral differentiation of regulatory T cells.
Natural Th 17 cells are critically regulated by functional medullary thymic
TLDR
It is revealed thatThymic stromal MHC class II expression and RelB-dependent medullary thymic epithelial cells (mTEC), including Aireþ mTEC, are an essential requirement for nTh17 development, which demonstrates a partial, non-redundant requirement for both ICOS-ligand and CD80/86 costimulation.
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References

SHOWING 1-10 OF 56 REFERENCES
Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells
TLDR
It is found that an absence of major histocompatibility class II molecules on mTECs resulted in fewer polyclonal regulatory T cells and targeting of a model antigen to Aire+ mT ECs led to the generation of specific regulatory T Cells independently of antigen transfer to dendritic cells.
CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium.
Differentiation of regulatory Foxp3+ T cells in the thymic cortex
TLDR
It is reported that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting TR differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction.
Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity.
Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation
TLDR
It is shown that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells and BM- derived cells extend the range of clonal deletion by cross-presenting antigen captured from MTecs.
The thymic medulla: a unique microenvironment for intercellular self-antigen transfer
TLDR
Evidence is provided for a unique, constitutive, and unidirectional transfer of self-antigens within the thymic microenvironment, thus broadening the cellular base for tolerance induction toward promiscuously expressed tissue antigens.
Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control
TLDR
It is proposed that the intrinsically high predisposition of immature thymocytes to Treg development may contribute to the predominantly thymic origin of the Treg repertoire.
Intercellular MHC transfer between thymic epithelial and dendritic cells
TLDR
This work shows the functional intercellular transfer of membrane material, including MHC molecules, occurring between epithelial cells and, in a polarized fashion, from epithelial to DC, in what might participate to the process of negative selection in the thymic medulla.
Sampling of complementing self‐antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance
TLDR
It is shown that antigen expression in a minor fraction of medullary thymic epithelial cells leads to deletion of specific CD4 T cells, and this deletion is not dependent on cross‐presentation by hemopoietic antigen‐presenting cells, which have been ascribed a predominant role in negative selection.
Major Histocompatibility Complex Class II–Positive Cortical Epithelium Mediates the Selection of Cd4+25+ Immunoregulatory T Cells
TLDR
It is found that CD4+25+ T cells are present in the thymus and periphery of K14-Aβ b and H2-DMα–deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4-25− effector T cells.
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