Thymic epithelial cells require p53 to support their role in T-cell development and tolerance induction.

Thymic epithelial cells (TECs) constitute crucial microenvironments for T-cell development and self-tolerance. Beyond its recognized tumor suppressive function, p53 regulates the differentiation of multiple cell lineages. To study the cell-autonomous role of p53 in thymic epithelial homeostasis, we analyzed mice with conditional inactivation of Trp53 in TECs (p53cKO) and reported that p53 is a key regulator of medullary TEC (mTEC) integrity. We found that p53 controls the expression and responsiveness of RANK, which is crucial for mTEC differentiation. Genome-wide analysis showed the global impact of p53 in coordinating distinct branches of the mTEC transcriptional program. Besides failures in sustaining adult thymopoiesis, defects in mTEC-dependent regulatory T-cell development and thymocyte maturation unfold in mutant thymus. Concurrently, manifestations of aberrant self-tolerance emerge with age or upon transfer of p53cKO-derived thymocytes into immunodeficient mice. Our findings position p53 as a prime determinant in maintaining the regular and tolerogenic thymic function across life.