TGF-β controls development of TCRγδ⁺CD8αα⁺ intestinal intraepithelial lymphocytes

γδ intestinal intraepithelial lymphocytes (IELs) constitute the majority of IELs with unique CD8αα⁺ homodimers that are distinct from γδT cells in other tissues. However, it remains largely unclear how those cells develop. Here we show that transforming growth factor beta (TGF-β) signaling controls the development of TCRγδ⁺CD8αα⁺ IELs. Deletion of TGF-β receptors or Smad3 and Smad2 in bone marrow stem cells caused a deficiency of TCRγδ⁺CD8αα⁺ IELs in mixed bone marrow chimeric mice. Mechanistically, TGF-β is required for the development of TCRγδ⁺CD8αα⁺ IELs thymic precursors (CD44^-CD25^- γδ thymocytes). In addition, TGF-β signaling induced CD8α in thymic γδT cells and maintained CD8α expression and survival in TCRγδ⁺CD8αα⁺ IELs. Moreover, TGF-β also indirectly controls TCRγδ⁺CD8αα⁺ IELs by modulating the function of intestinal epithelial cells (IECs). Importantly, TGF-β signaling in TCRγδ⁺CD8αα⁺ IELs safeguarded the integrity of the intestinal barrier in dextran sulfate sodium (DSS)-induced colitis.