Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells

Abstract

Although Notch signaling plays important roles in lineage commitment and differentiation of multiple cell types including conventional T cells, nothing is currently known concerning Notch function in innate-like T cells. We have found that the homeostasis of several well-characterized populations of innate-like T cells including invariant NKT cells (iNKT), CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells is controlled by Notch. Notch selectively regulates hepatic iNKT cell survival via tissue-restricted control of B cell lymphoma 2 and IL-7Rα expression. More generally, Notch regulation of innate-like T cell homeostasis involves both cell-intrinsic and -extrinsic mechanisms and relies upon context-dependent interactions with Notch ligand-expressing fibroblastic stromal cells. Collectively, using conditional ablation of Notch receptors on peripheral T cells or Notch ligands on putative fibroblastic stromal cells, we show that Notch signaling is indispensable for the homeostasis of three tissue-restricted populations of innate-like T cells: hepatic iNKT, CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells, thus supporting a generalized role for Notch in innate T cell homeostasis.

Notch Signaling and Immune Regulation in Alloimmunity

“…In another study, RORγt + ILCs near the marginal zone were shown to stimulate marginal zone B cells via production of B cell-activation factor (BAFF), co-stimulatory receptor ligand CD40L and DLL1 (45), providing an evidence of crosstalk between innate and adaptive immune system. Lastly, T-cell specific Notch1/2 deletion as well as FRC-specific ( Ccl19 -Cre) DLL1 or DLL4 deletion led to severe reduction, both in number and in function, of hepatic invariant NKT (iNKT) cells, CD8ααTCRαβ small intestinal intraepithelial lymphocytes and innate memory phenotype CD8 T cells, providing another line of evidence that Notch signaling is indispensable for innate-like T cells differentiation and function (46). …”