scholarly journals Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

2013 ◽  
Vol 200 (4) ◽  
pp. i8-i8
Author(s):  
Martin Aichinger ◽  
Chunyan Wu ◽  
Jelena Nedjic ◽  
Ludger Klein
Keyword(s):  
Epithelial Cells ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Medullary Thymic Epithelial Cells

scholarly journals Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

2013 ◽  
Vol 210 (2) ◽  
pp. 287-300 ◽  
Author(s):  
Martin Aichinger ◽  
Chunyan Wu ◽  
Jelena Nedjic ◽  
Ludger Klein
Keyword(s):  
Epithelial Cells ◽  
Mhc Class Ii ◽  
Negative Selection ◽  
Class Ii ◽  
Single Amino Acid ◽  
Thymic Epithelial Cells ◽  
Clonal Deletion ◽  
Central Tolerance ◽  
Metabolic Functions ◽  
Physiological Relevance

Macroautophagy serves cellular housekeeping and metabolic functions through delivery of cytoplasmic constituents for lysosomal degradation. In addition, it may mediate the unconventional presentation of intracellular antigens to CD4+ T cells; however, the physiological relevance of this endogenous MHC class II loading pathway remains poorly defined. Here, we characterize the role of macroautophagy in thymic epithelial cells (TECs) for negative selection. Direct presentation for clonal deletion of MHC class II–restricted thymocytes required macroautophagy for a mitochondrial version of a neo-antigen, but was autophagy-independent for a membrane-bound form. A model antigen specifically expressed in Aire+ medullary TECs (mTECs) induced efficient deletion via direct presentation when targeted to autophagosomes, whereas interference with autophagosomal routing of this antigen through exchange of a single amino acid or ablation of an essential autophagy gene abolished direct presentation for negative selection. Furthermore, when this autophagy substrate was expressed by mTECs in high amounts, endogenous presentation and indirect presentation by DCs operated in a redundant manner, whereas macroautophagy-dependent endogenous loading was essential for clonal deletion at limiting antigen doses. Our findings suggest that macroautophagy supports central CD4+ T cell tolerance through facilitating the direct presentation of endogenous self-antigens by mTECs.

scholarly journals Positive Selection by Purified MHC Class II / Thymic Epithelial CellsIn Vitro: Costimulatory Signals Mediated by B7 Are Not Involved

1994 ◽  
Vol 3 (4) ◽  
pp. 265-271 ◽  
Author(s):  
Eric J. Jenkinson ◽  
Graham Anderson ◽  
Nel C. Moore ◽  
Christopher A. Smith ◽  
John J. T. Owen
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Positive Selection ◽  
Mhc Class Ii ◽  
Functional Capacity ◽  
T Cell Development ◽  
Class Ii ◽  
Thymic Epithelial Cells ◽  
Costimulatory Signals

We have investigated the possibility that the costimulatory signals required for activation of mature T cells also play a role in providing differentiation signals for positive selection during T-cell development. We show that purified MHC Class II+thymic epithelial cells are able to support positive selectionin vitrobut lack both the functional capacity to deliver costimulatory signals and expression of the costimulatory ligand B7. Our results suggest that the additional signals provided by costimulatory ligands are not required for TCR-mediated positive selection, although other ancillary signals provided by thymic epithelial cells may be involved.

scholarly journals Prss16 Is Not Required for T-Cell Development

2005 ◽  
Vol 25 (2) ◽  
pp. 789-796 ◽  
Author(s):  
Saijai Cheunsuk ◽  
Zhe-Xiong Lian ◽  
Guo-Xiang Yang ◽  
M. Eric Gershwin ◽  
Jeffrey R. Gruen ◽  
...  
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Mhc Class Ii ◽  
T Cell Development ◽  
Surface Expression ◽  
Class Ii ◽  
Cell Development ◽  
Thymic Epithelial Cells ◽  
Wild Type ◽  
Thymic Development

ABSTRACT PRSS16 is a serine protease expressed exclusively in cortical thymic epithelial cells (cTEC) of the thymus, suggesting that it plays a role in the processing of peptide antigens during the positive selection of T cells. Moreover, the human PRSS16 gene is encoded in a region near the class I major histocompatibility complex (MHC) that has been linked to type 1 diabetes mellitus susceptibility. The mouse orthologue Prss16 is conserved in genetic structure, sequence, and pattern of expression. To study the role of Prss16 in thymic development, we generated a deletion mutant of Prss16 and characterized T-lymphocyte populations and MHC class II expression on cortical thymic epithelial cells. Prss16-deficient mice develop normally, are fertile, and show normal thymic morphology, cellularity, and anatomy. The total numbers and frequencies of thymocytes and splenic T-cell populations did not differ from those of wild-type controls. Surface expression of MHC class II on cTEC was also similar in homozygous mutant and wild-type animals, and invariant chain degradation was not impaired by deletion of Prss16. These findings suggest that Prss16 is not required for quantitatively normal T-cell development.

Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance

2011 ◽  
Vol 32 (5) ◽  
pp. 188-193 ◽  
Author(s):  
Ludger Klein ◽  
Maria Hinterberger ◽  
Julia von Rohrscheidt ◽  
Martin Aichinger
Keyword(s):  
Dendritic Cell ◽  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Medullary Thymic Epithelial Cells

scholarly journals Post-Aire Medullary Thymic Epithelial Cells and Hassall’s Corpuscles as Inducers of Tonic Pro-Inflammatory Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Martti Laan ◽  
Ahto Salumets ◽  
Annabel Klein ◽  
Kerli Reintamm ◽  
Rudolf Bichele ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tolerance Induction ◽  
Convincing Evidence ◽  
Keratinocyte Differentiation ◽  
Thymic Epithelial Cells ◽  
Special Focus ◽  
Central Tolerance ◽  
Inflammatory Microenvironment ◽  
Medullary Thymic Epithelial Cells ◽  
Late Stages

While there is convincing evidence on the role of Aire-positive medullary thymic epithelial cells (mTEC) in the induction of central tolerance, the nature and function of post-Aire mTECs and Hassall’s corpuscles have remained enigmatic. Here we summarize the existing data on these late stages of mTEC differentiation with special focus on their potential to contribute to central tolerance induction by triggering the unique pro-inflammatory microenvironment in the thymus. In order to complement the existing evidence that has been obtained from mouse models, we performed proteomic analysis on microdissected samples from human thymic medullary areas at different differentiation stages. The analysis confirms that at the post-Aire stages, the mTECs lose their nuclei but maintain machinery required for translation and exocytosis and also upregulate proteins specific to keratinocyte differentiation and cornification. In addition, at the late stages of differentiation, the human mTECs display a distinct pro-inflammatory signature, including upregulation of the potent endogenous TLR4 agonist S100A8/S100A9. Collectively, the study suggests a novel mechanism by which the post-Aire mTECs and Hassall’s corpuscles contribute to the thymic microenvironment with potential cues on the induction of central tolerance.

scholarly journals Contrasting models of promiscuous gene expression by thymic epithelium

2005 ◽  
Vol 202 (1) ◽  
pp. 15-19 ◽  
Author(s):  
Geoffrey O. Gillard ◽  
Andrew G. Farr
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Broad Spectrum ◽  
Alternative Model ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Thymic Epithelium ◽  
Medullary Thymic Epithelial Cells ◽  
Promiscuous Gene Expression ◽  
Self Antigens

Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted self-antigens (TRAs), which are required for the development of central tolerance. A new study suggests that TRA expression is a specialized property of terminally differentiated mTECs. However, as discussed here, an alternative model—whereby TRA expression is regulated by conserved developmental programs active in developing mTECs—may be equally plausible.

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