Foxp1 controls Fezf2-dependent gene expression, mimetic mTEC diversity, and thymic central tolerance.

Forkhead Box P1 (Foxp1) is a transcription factor critical for the proper development of multiple tissues. While Foxp1 has a well-described role in regulating adaptive immunity through modulation of T and B cells, a function in medullary thymic epithelial cells (mTECs) has not been reported. Here we show that Foxp1 is expressed in mTECs and deletion of Foxp1 in TECs results in significant changes to mTEC populations. Surprisingly, Foxp1-deletion results in an expansion of neuroendocrine mTECs and Ccl21a-expressing mTECs and a loss of Aire mTECs, tuft cells, and microfold mTECs. With these changes in mimetic mTECs there are alterations to the thymus with enhanced thymic size, shifts in thymic innate lymphocyte populations, and loss of thymic B cell class switching. Mechanistically, scRNA-seq gene expression analysis of mTECs reveals decreased Fezf2 gene expression with loss of Foxp1 in mTECs resulting in attenuated Fezf2-induced tissue specific antigen gene expression, and autoimmunity in aged mice. Altogether, our studies reveal that Foxp1 moderates mimetic mTECs and Fezf2-dependent gene expression resulting in significant changes to mTEC population diversity.