RNA-binding proteins Zfp36l1 and Zfp36l2 protect against premature thymic involution.

The thymus is a primary lymphoid organ that undergoes progressive age-associated involution, leading to reduced T cell output and impaired adaptive immunity. In this study, we employed scRNA-Seq as well as other approaches to reveal that medullary thymic epithelial cells (mTECs) produce excessive proinflammatory cytokines in the absence of Zfp36l1 and Zfp36l2, two RNA-binding proteins of TTP family. Consequently, FOXN1, a master regulator of pro-lymphopoietic genes in thymic epithelial cells, was down-regulated in young mice, which leads to premature thymic involution in knockout mice. These findings reveal a protective role for TTP family proteins in regulating cytokine levels within the thymic microenvironment and preventing premature thymic involution. Overall design: Thymic epithelial cells (TECs) from 3 postnatal day 6 conditional double knockout mice that specifically delete Zfp36l1 and Zfp36l2 in TECs and 3 floxed control mice were isolated by fluorescence-activated cell sorting (FACS) and analyzed by scRNA-Seq