Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens

The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.

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“…4B and fig. S24), suggesting that they may correspond to the previously described AIRE + CCR7 + DCs in human tonsils and thymus (61).…”

Section: Recruitment and Activation Of Dcs For Thymocyte Selectionsupporting

confidence: 55%

A cell atlas of human thymic development defines T cell repertoire formation

Park

Botting

Conde

et al. 2020

Science

510

569

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“…4B and fig. S9), suggesting that they may include the previously described AIRE + CCR7 + DCs in human tonsils and thymus (45).…”

Section: Recruitment and Activation Of Dcs For Thymocyte Selectionmentioning

confidence: 74%

A cell atlas of human thymic development defines T cell repertoire formation

Park

Botting

Conde

et al. 2020

Preprint

109

168

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The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We utilised single-cell RNA-sequencing (scRNA-seq) to create a cell census of the human thymus and to reconstruct T-cell differentiation trajectories and T-cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ novel CD8αα + T-cell populations, thymic fibroblast subtypes and activated dendritic cell (aDC) states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and suggests later commitment of the CD8 + T-cell lineage. Taken together, our data provide a comprehensive atlas of the human thymus across the lifespan with new insights into human T-cell development.Main Text:

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“…To ascertain if the expression of discrete ERE families was restricted to specific tissues, we computed the τ index of tissue specificity as defined by Yanai et al [33]. Briefly, the τ index compares the expression of a gene in a set of tissues and has a value ≤ 0.4 for housekeeping genes and ≥ 0.8 for tissuerestricted genes [54]. We identified a total of 124 ERE families with a tissue-restricted expression.…”

Section: Most Human Tissues Show a Tissue-specific Ere Expressionmentioning

confidence: 99%

Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues

et al. 2020

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Background: Endogenous retroelements (EREs) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. The dominant paradigm holds that EREs are expressed in embryonic stem cells (ESCs) and germline cells but are repressed in differentiated somatic cells. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a systemlevel evaluation of their expression in human tissues is lacking. Methods: Using RNA sequencing data, we analyzed ERE expression in 32 human tissues and cell types, including medullary thymic epithelial cells (mTECs). A tissue specificity index was computed to identify tissue-restricted ERE families. We also analyzed the transcriptome of mTECs in wild-type and autoimmune regulator (AIRE)-deficient mice. Finally, we developed a proteogenomic workflow combining RNA sequencing and mass spectrometry (MS) in order to evaluate whether EREs might be translated and generate MHC I-associated peptides (MAP) in Blymphoblastoid cell lines (B-LCL) from 16 individuals. Results: We report that all human tissues express EREs, but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC I-deficient tissues (ESCs and testis) and one MHC I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. Conclusions: This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.

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Maturing Human CD127+ CCR7+ PDL1+ Dendritic Cells Express AIRE in the Absence of Tissue Restricted Antigens

Cited by 43 publications

References 55 publications

A cell atlas of human thymic development defines T cell repertoire formation

A cell atlas of human thymic development defines T cell repertoire formation

A cell atlas of human thymic development defines T cell repertoire formation

Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues

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