Longevity & AgingTwo Waves of Thymic Mimetic Cells Reveal How Immune Tolerance Evolved
Thymic mimetic cells — rare thymus-resident cells that mimic peripheral tissues to train self-tolerant T cells — develop in two distinct waves in mice. Prenatal cells mimic muscle, goblet, ionocyte, and ciliated tissues, while postnatal cells mimic enterohepatic and skin keratinocyte types. The transcription factor FOXN1 is required for postnatal but not prenatal mimetic cells. Cross-species experiments, including replacing mouse Foxn1 with genes from amphioxus and cartilaginous fish, revealed that this postnatal wave is a vertebrate-specific innovation. Even jawless vertebrates like lampreys harbor thymus-like cells expressing liver-specific proteins, suggesting tolerance to newer tissue types co-evolved with FOXN1 itself. These findings provide a framework for understanding how central immune tolerance was built incrementally across vertebrate evolution.
