Abstract
The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies. Foxn1 is a transcription factor that is essential for thymus organogenesis; however, the direct target for Foxn1 to actuate thymic T-cell production is unknown. Here we show that a Foxn1-binding cis-regulatory element promotes the transcription of β5t, which has an essential role in cortical thymic epithelial cells to induce positive selection of functionally competent CD8+ T cells. A point mutation in this genome element results in a defect in β5t expression and CD8+ T-cell production in mice. The results reveal a Foxn1-β5t transcriptional axis that governs CD8+ T-cell production in the thymus.
Highlights
The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies
Positive selection of functionally competent CD8 þ T cells is dependent on TCR engagement of immature thymocytes with self-peptides produced by the thymoproteasome, a thymus-specific form of the proteasome[6,7,8,9,10]
The thymoproteasome is expressed in cortical thymic epithelial cells because its unique catalytic subunit b5t or Psmb[11] is exclusively transcribed in cTECs11–14
Summary
The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies. We show that a Foxn1-binding cis-regulatory element promotes the transcription of b5t, which has an essential role in cortical thymic epithelial cells to induce positive selection of functionally competent CD8 þ T cells. Like b5t, many molecules, including DLL4, CCL25 and PD-L1, expressed in TECs have markedly reduced expression in Foxn1-deficient mouse thymus[17,18,19,20] It is not established whether Foxn[1] directly or indirectly affects the expression of any of those TEC-associated genes, including functionally relevant genes in the thymus. In vivo experiments in mouse show that this cis-regulatory element is essential for the optimal expression of b5t in cTECs and the optimal production of CD8 þ T cells. Our results reveal a Foxn1-binding cis-regulatory element that is functionally relevant for the thymus to produce T cells
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