TGF-beta controls development of TCR gamma delta(+)CD8 alpha alpha(+) intestinal intraepithelial lymphocytes

gamma delta intestinal intraepithelial lymphocytes (IELs) constitute the majority of IELs with unique CD8 alpha alpha(+) homodimers that are distinct from gamma delta T cells in other tissues. However, it remains largely unclear how those cells develop. Here we show that transforming growth factor beta (TGF-beta) signaling controls the development of TCR gamma delta(+)CD8 alpha alpha(+) IELs. Deletion of TGF-beta receptors or Smad3 and Smad2 in bone marrow stem cells caused a deficiency of TCR gamma delta(+)CD8 alpha alpha(+) IELs in mixed bone marrow chimeric mice. Mechanistically, TGF-beta is required for the development of TCR gamma delta(+)CD8 alpha alpha(+) IELs thymic precursors (CD44(-)CD25(-) gamma delta thymocytes). In addition, TGF-beta signaling induced CD8 alpha in thymic gamma delta T cells and maintained CD8 alpha expression and survival in TCR gamma delta(+)CD8 alpha alpha(+) IELs. Moreover, TGF-beta also indirectly controls TCR gamma delta(+)CD8 alpha alpha(+) IELs by modulating the function of intestinal epithelial cells (IECs). Importantly, TGF-beta signaling in TCR gamma delta(+)CD8 alpha alpha(+) IELs safeguarded the integrity of the intestinal barrier in dextran sulfate sodium (DSS)-induced colitis.