Interplay between Follistatin, Activin A, and BMP4 Signaling Regulates Postnatal Thymic Epithelial Progenitor Cell Differentiation during Aging

Abstract

Summary: A key feature of immune functional impairment with age is the progressive involution of thymic tissue responsible for naive T cell production. In this study, 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 bipotent TEC progenitor differentiation and depletion of Sca-1lo 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. : Mechanisms underlying age-associated thymic involution remain elusive. Here, Lepletier et al. show that an imbalance in activin A and BMP4 signaling drives thymic involution. This occurs in two major stages: impairment of medullary TEC differentiation and initiation of TEPC quiescence, followed by the broader, negative impact of reduced lineage committed precursors. Keywords: thymus, thymic involution, thymic epithelial cells, thymic epithelial progenitor, BMP4, activin A, follistatin, immune aging, thymus regeneration, androgen blockade