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Thymic regeneration is a crucial function that allows for the generation of mature T cells after myelosuppression

like irradiation. However molecular drivers involved in this process remain undefined. Here,

we report that the angiogenic factor, epidermal growth factor-like domain 7 (Egfl7), is expressed on

steady state thymic endothelial cells (ECs) and further upregulated under stress like post-irradiation.

Egfl7 overexpression increased intrathymic early thymic precursors (ETPs) and expanded thymic ECs.

Mechanistically, we show that Egfl7 overexpression caused Flt3 upregulation in ETPs and thymic ECs, and

increased Flt3 ligand plasma elevation in vivo. Selective Flt3 blockade prevented Egfl7-driven ETP

expansion, and Egfl7-mediated thymic EC expansion in vivo. We propose that the angiogenic factor Egfl7

activates the Flt3/Flt3 ligand pathway and is a key molecular driver enforcing thymus progenitor generation

and thereby directly linking endothelial cell biology to the production of T cell-based adaptive

immunity.

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