Interplay between Follistatin, Activin A and Bmp4 Signaling Regulates Postnatal Thymic Epithelial Progenitor Cell Differentiation During Aging

Abstract

One of the key features of immune functional impairment with age is the progressive involution of the 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, with depletion of Sca-1lo cTEC and mTEC lineage-specific precursors. We reveal the increased production of follistatin by aging TECs contributes to their own demise. This TEC loss occurs primarily through antagonism of activin A signaling, which we show is required for TEC maturation and acts in dissonance to Bmp4. Together, these results indicate that an imbalance of activin A and Bmp4 signaling underpins degeneration of postnatal TEC maintenance during aging, and its reversal enables transient replenishment of mature TECs.