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 Quantitative Analysis of the Efficiency of Clonal Deletion in the Thymus

1994 ◽  
Vol 4 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Lisa M. Spain ◽  
Leslie J. Berg
Keyword(s):  
Epithelial Cells ◽  
Mhc Class Ii ◽  
Negative Selection ◽  
Gene Dosage ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Clonal Deletion ◽  
Self Tolerance ◽  
Antigen Presenting ◽  
Mhc Class Ii Molecules

One of the major mechanisms for establishing self-tolerance is the clonal deletion of self-reactive T cells during their development in the thymus. Using a TCR transgenic mouse model, we have established a quantitativeex vivoassay for examining the sensitivity and specificity of negative selection. Thymic organ cultures established from mice of varying MHC haplotypes were incubated with antigen, and the efficiency of clonal deletion assessed. We show here that clonal deletion of CD4+8+thymocytes is sensitive to both the gene dosage and the allelic variation of MHC class II molecules expressed on thymic antigen-presenting cells. We also find that when epithelial cells in the thymic cortex are the only antigen-presenting cells expressing the appropriate MHC class II molecules, negative selection of CD4+8+cells is as efficient as when antigen is presented on all thymic antigen-presenting cells. These studies demonstrate that the induction of self-tolerance via clonal deletion in the thymus is a function not only of antigen concentration, but also of MHC class II cell-surface density. In addition, together with the reports of others, these results confirm that cortical epithelial cells can mediate negative selection, and demonstrate that they do so in the intact thymic microenvironment.

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.

scholarly journals Thymic rejuvenation via induced thymic epithelial cells (iTECs) from FOXN1-overexpressing fibroblasts to counteract inflammaging

2020 ◽  
Author(s):  
Jiyoung Oh ◽  
Weikan Wang ◽  
Rachel Thomas ◽  
Dong-Ming Su
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Negative Selection ◽  
De Novo ◽  
The Elderly ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Embryonic Fibroblasts ◽  
Central Tolerance ◽  
Age Related

AbstractAge-associated systemic, chronic, sterile inflammatory condition (inflammaging) is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. Age-related thymic involution causally results from gradually declined expression of the transcription factor forkhead box N1 (FOXN1) in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can significantly rescue age-related thymic involution. Given the findings that induced TECs (iTECs) from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected natural young TECs can lead to middle-aged thymus regrowth, we sought to expand upon these two findings by applying them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated iTECs. We engrafted iTECs, rather than natural young TECs, directly into the aged thymus and/or peri-thymus and found a significantly rejuvenated architecture and function in the native aged murine thymus. The engrafted iTECs drove regrowth of the aged thymus in both male and female mice, showing not only increased thymopoiesis, but also reinforcement of thymocyte negative selection, thereby, reducing senescent T cells and auto-reactive T cell-mediated inflammaging phenotypes in old mice. Therefore, this is a promising thymic rejuvenation strategy with preclinical significance, which can potentially rescue declined thymopoiesis and impaired negative selection to significantly, albeit partially, restore the defective central tolerance and reduce subclinical chronic inflammatory symptoms in the elderly.Graphical AbstractA novel rejuvenation strategy via the FOXN1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts (termed iTECs) by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.

scholarly journals Thymus Medulla Formation and Central Tolerance Are Restored in IKKα−/− Mice That Express an IKKα Transgene in Keratin 5+ Thymic Epithelial Cells

2007 ◽  
Vol 178 (2) ◽  
pp. 829-837 ◽  
Author(s):  
Dakshayani Lomada ◽  
Bigang Liu ◽  
Lezlee Coghlan ◽  
Yinling Hu ◽  
Ellen R. Richie
Keyword(s):  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Keratin 5
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