Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Abstract

15Ageing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell 16 death and compromised organ function. This is first observed in the thymus, the primary 17 lymphoid organ that generates and selects T cells. However, the molecular and cellular 18 mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse 19 ageing leads to less efficient T cell selection, decreased self-antigen representation and 20 increased T cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and 21 lineage-tracing, we find that progenitor cells are the principal targets of ageing, whereas the 22 function of mature thymic epithelial cells is compromised only modestly. Specifically, an early-23 life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished 24 at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance 25 2 of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs 26 the core immunological functions of the thymus. 27 28

A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency

“…This alteration in the mTEC compartment impaired both the expression of FOXN1 target genes (Figure 2fi) [2]and AIRE-controlled tissuerestricted antigens (Figure 2fii) [25]. Moreover, mature mTEC isolated from FOXN1 WT/Δ505 mice at either 5-or 16-weeks of age showed evidence of accelerated ageing in comparison to controls [1,26] thus suggesting that cells passing through the mTEC developmental block were under increased cellular stress (Figure 2fiii). In .…”

“…To further probe the consequences of Δ505 Foxn1 heterozygosity for TEC differentiation, we assessed the transcriptome of single epithelial cells using a recently published data set as reference to infer distinct TEC subtypes [1]. The composition of the TEC scaffold was significantly changed in mutant mice, affecting the frequency of all but one of the TEC subtypes (i.e.…”

“…Cells from individual 10X Chromium lanes were combined using canonical correlation analysis-based integration in Seurat (version 3.1.1) [55]. Cell clusters were identified using the default resolution of 0.8 and visualized using UMAP Cell type annotation was based on projection from our previously published reference data [1]along with manual annotation of non-TEC . CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…The thymus microenvironment promotes the development of naïve T cells with a repertoire purged of "self" specificities and poised to react to potentially injurious "non-self" threats. Thymic epithelial cells (TEC) constitute the major component of the thymic stroma and can be categorised into separate lineages and states based on their specific molecular, structural, and functional characteristics [1]. TEC differentiation, maintenance, and function critically rely on the transcription factor FOXN1 [2][3][4][5][6][7][8].…”

The thymus and the science of self

“…Fezf2 has originally been identified to be required for brain differentiation and specification [73] and thus also serves purpose outside of the thymus, similar to AIRE. Notably, neither Aire nor Fezf2 transcription is changed with age (at least in mouse) but PGE of AIRE-controlled genes is diminished at later ages, suggesting a mechanism of transcription that is also reliant on factors other than AIRE abundance [74]. This mechanism still awaits to be precisely defined.…”