Biology subjects

Richie, E. R.

Publications and source records attributed to Richie, E. R..

3 recordsLinked to original sources

bioRxiv2023

Transposable elements regulate thymus development and function

Transposable elements (TE) are repetitive sequences representing [~]45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTEC). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN LJ/{beta}. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.

immunology↗

bioRxiv2022

An early decline in ETPs reflects reduced pre-thymic progenitors and altered signals from the thymus microenvironment

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens. Elucidating mechanisms underlying involution will inform strategies to restore thymopoiesis. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find ETP cellularity declines as early as 3 months (3MO) in mice. This initial ETP reduction could reflect changes in pre-thymic progenitors and/or thymic stromal niches. We demonstrate that the number of functional TSP/ETP niches is not reduced with age. Instead, the number of pre-thymic BM and circulating lymphoid progenitors is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM progenitors and ETPs declines by 3MO, indicating defective niche quality contributes to the reduction in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to the initial decline in ETPs, setting the stage for progressive thymus involution. Summary statementThe number of early T-cell progenitors declines by 3 months of age in mice. This decline reflects a sharp drop in circulating thymus seeding progenitors, fewer bone marrow lymphoid progenitors, and reduced Notch signaling in both bone marrow and thymus.

immunology↗

bioRxiv2022

Central tolerance is impaired in the middle-aged thymic environment

One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymic microenvironment. Thymic T-cell export continues into adulthood, yet the impact of thymic involution on the quality of newly generated T-cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue restricted antigens (TRAs) decline with age, suggesting the involuting thymus may not promote efficient central tolerance. Here, we demonstrate that the middle-aged thymic environment does not support rapid motility of medullary thymocytes, potentially diminishing their ability to scan antigen presenting cells that display the diverse self-antigens that induce central tolerance. Consistent with this possibility, thymic slice assays reveal that the middle-aged thymic environment does not support efficient negative selection or regulatory T cell (Treg) induction of thymocytes responsive to either TRAs or ubiquitous self-antigens. This decline in central tolerance is not universal, but instead impacts lower-avidity self-antigens that are either presented at low levels or bind to TCRs with moderate affinities. Additionally, the decline in thymic tolerance by middle-age is accompanied by both a reduction in mTECs and hematopoietic antigen presenting cell subsets that cooperate to drive central tolerance. Thus, age-associated changes in the thymic environment result in impaired central tolerance against moderate avidity self-antigens, potentially resulting in export of increasingly autoreactive naive T cells, with a deficit of Treg counterparts by middle age.

immunology↗