A Better Understanding of the Mechanisms Surrounding Thymic Involution

A Better Understanding of the Mechanisms Surrounding Thymic Involution

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Researchers here report on their exploration of the protein interactions involved in the loss of active thymic tissue with age, a process called thymic involution. Since the thymus is where T cells mature, this loss contributes to the age-related decline of the adaptive immune system. Historically, this sort of investigation has focused on FOXN1 as the master regulator of thymic growth and activity. Upstream of FOXN1 is BMP4, however, and the paper here discusses the ways in which BMP4 is dysregulated with age. This discussion should probably be read in the context of other work that strongly suggests chronic inflammation is the driver of changes leading to thymic involution. Nothing happens in isolation in aging tissues, and there are usually deeper causes to be considered.

Thymic epithelial cells (TECs) are essential for the establishment of the specialized microenvironment that orchestrates the development of naive, self-tolerant T cells from hematopoietic precursors. They are supported by non-epithelial thymic stromal cells (TSCs), such as fibroblasts and endothelial cells, in an extracellular matrix-rich three-dimensional (3D) scaffold structure. TECs can be broadly divided into functionally and spatially distinct cortical (cTEC) and medullary (mTEC) subsets. Thymic epithelial progenitor cells (TEPC) support the development of both cTECs and mTECs during thymus organogenesis.

Deterioration of thymus function occurs naturally during aging and ultimately constrains the host immune repertoire. It is characterized by a reduction in total thymic cellularity and naive T cell production. Reduced TEC turnover and diminished levels of transcription factor forkhead-box N1 (FOXN1), a master regulator of TEC lineage specification, have been observed in the aged thymus. An increase in steroidal hormone production at puberty has also been implicated in age-related thymus involution, with androgen deprivation (AD) inducing the recovery of naive T cell production and bone marrow function in aged male mice and in humans. However, the mechanisms and signaling pathways causing the post-pubertal loss of specific TECs and underpinning AD-induced thymocyte regeneration remain unclear.

In this study, we examined numeric, phenotypic, and transcriptomic alterations in TEC and non-TEC (non-epithelial stromal cells, fibroblasts, and endothelial cells) stromal subsets during age-related thymic involution, and following transient thymic recovery via AD. We identify two major phases of thymic epithelial cell (TEC) loss during aging: a block in mature TEC differentiation from the pool of immature precursors, occurring at the onset of puberty, followed by impaired TEC progenitor differentiation and depletion of cTEC and mTEC lineage-specific precursors. We reveal that an increase in follistatin production by aging TECs contributes to their own demise. TEC loss occurs primarily through the antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to BMP4, which promotes the maintenance of TEC progenitors. These results support a model in which an imbalance of activin A and BMP4 signaling underpins the degeneration of postnatal TEC maintenance during aging, and its reversal enables the transient replenishment of mature TECs.

Link: https://doi.org/10.1016/j.celrep.2019.05.045

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