Biology subjects

Selden, H. J.

Publications and source records attributed to Selden, H. J..

3 recordsLinked to original sources

bioRxiv2022

CCR4 and CCR7 differentially regulate thymocyte subset localization with distinct outcomes for central tolerance

Central tolerance ensures autoreactive T cells are eliminated or diverted to the regulatory T cell lineage, thus preventing autoimmunity. To undergo central tolerance, thymocytes must enter the medulla to test their TCRs for autoreactivity against the diverse self-antigens displayed by antigen presenting cells (APCs). While CCR7 is known to promote thymocyte medullary entry and negative selection, our previous studies implicate CCR4 in these processes, raising the question of whether CCR4 and CCR7 play distinct or redundant roles in central tolerance. Here, synchronized positive selection assays, 2-photon timelapse microscopy, and quantification of TCR-signaled apoptotic thymocytes, demonstrate that CCR4 and CCR7 promote medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets. CCR4 is upregulated within hours of positive selection signaling and promotes medullary entry and clonal deletion of immature post-positive selection thymocytes. In contrast, CCR7 is expressed several days later and is required for medullary localization and negative selection of mature thymocytes. In addition, CCR4 and CCR7 differentially enforce self-tolerance, with CCR4 enforcing tolerance to self-antigens presented by activated APCs, which express CCR4 ligands. Our findings show that CCR7 expression is not synonymous with medullary localization and support a revised model of central tolerance in which CCR4 and CCR7 promote early and late stages of negative selection, respectively, via interactions with distinct APC subsets.

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↗