TGF-β controls development of TCRγδ+CD8αα+ intestinal intraepithelial lymphocytes
Jiajia Han, Na Liu, Wenwen Jin, Peter Zanvit, Dunfang Zhang, Junji Xu, Andrew Bynum, Rida Kazmi, Jianmin Zhang, Wei He, WanJun Chen
Abstract
Abstract 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.