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Proteasome alteration between epithelial and hematopoietic cells facilitates positive selection of CD8 T cells

ABSTRACT: The thymoproteasome, a proteolytic complex uniquely expressed in cortical thymic epithelial cells (cTECs), governs the positive selection of CD8 T cells. It was hypothesized that the thymoproteasome promotes CD8 T cell development by forging a sequential switch between cTECs and medullary antigen-presenting cells (APCs), in which stepwise difference in MHC-I-associated peptides by cTECs and medullary APCs would spare positively selected thymocytes from subsequent negative selection. In this study, we engineered mice ectopically expressing thymoproteasomes in various APCs including medullary TECs (mTECs), eliminating the proposed proteasome switch. Surprisingly, we found that the proteasome switch between cTECs and mTECs was dispensable for thymoproteasome-dependent CD8 T cell development. Instead, we found that ectopic thymoproteasomes in hematopoietic cells impaired CD8 T cell development by hindering cortical positive selection.Our findings reveal that proteasome difference between cTECs and hematopoietic cells facilitates thymoproteasome-dependent positive selection in the thymic cortex.

ORGANISM(S): Mus musculus

PROVIDER: GSE322772 | GEO | 2026/03/24

REPOSITORIES: GEO

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Project description:Purpose: In all vertebrates, the thymus is necessary and sufficient for production of classic adaptive T cells. The key components of the thymus are cortical and medullary thymic epithelial cells (cTECs and mTECs). Despite the capital role of TECs, our understanding of TEC biology is quite rudimentary. For instance, we ignore what might be the extent of divergence in the functional program of these two TECs populations. It also remains unclear why the number of TECs decreases rapidly with age, thereby leading to progressive thymic insufficiency. Methods: Systems level understanding of cell function begins with gene expression profiling, and the transcriptome is currently the only '-ome' that can be reliably tackled in its entirety in freshly harvested primary cells. In order to gain novel insights into TEC biology, we therefore decided to analyse the whole transcriptome of cTECs, mTECs and skin epithelial cells. We elected to analyse gene expression using RNA-seq rather microarrays because RNA-seq has higher sensitivity and dynamic range coupled to lower technical variations. Results: Our deep sequencing approach provides a unique perspective into the transcriptome of TECs. Consistent with their ability to express ectopic genes, we found that mTECs expressed more genes than other cell populations. Out of a total of 15,069 genes expressed in TECs, 25% were differentially expressed by at least 5-fold in cTECs vs. mTECs. Genes expressed at higher levels in cTECs than mTECs regulate numerous cell functions including cell differentiation, cell movement and microtubule dynamics. Almost all positive regulators of the cell cycle were overexpressed in skin ECs relative to TECs. Conclusions: Our RNA-seq data provide novel insights into the transcriptional landscape of TECs, highlight substantial divergences in the transcriptome of TEC subsets and suggest that cell cycle progression is differentially regulated in TECS and skinECs. We believe that our work will therefore represent a valuable resource and will be of great interest to readers working in biological sciences, particularly in the areas of immunology and systems biology. The mRNA profiles of cTEC, mTEC (from 14 thymi of 7-days old C57BL/6 mice) and skinEC (from the trunk and dorsum of seven newborn mice) were generated by RNA-sequencing using Illumina HiSeq2000.

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Proteasome alteration between epithelial and hematopoietic cells facilitates positive selection of CD8 T cells

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