NKG2D is an activating receptor expressed on various immune cells. Engagement of NKG2D through its ligands, which are expressed mainly on transformed or stressed cells, typically leads to target cell death, thereby making it a potent player in anti-tumor immunity.

We recently identified a pro-tumor role for NKG2D in the context of inflammation-driven cancer, where sustained expression of NKG2D and its ligands resulted in exacerbated disease in a model of hepatocellular carcinoma

NKG2D has been implicated in various inflammatory disorders, where aberrant expression and activation of NKG2D-expressing effector cells can lead to tissue damage and autoinflammation. The intestine is of particular interest, as NKG2D ligands have been shown to be constitutively expressed on healthy epithelial cells. Further, NKG2D has been implicated in human inflammatory bowel disease. The role of NKG2D in colorectal cancer is unclear, but being an inflammation-driven cancer, we hypothesized that NKG2D would contribute and exacerbate intestinal tumorigenesis.

In this thesis, we show that NKG2D expression is elevated on various immune cells in the healthy murine intestine and confirm that germline deletion of NKG2D does not impact intestinal health at steady state. We further demonstrate that NKG2D exacerbates inflammation-driven intestinal cancer and identify CD8+ T cells and γδT cells as the main drivers of disease. We confirm that IFNγ-producing CD8+ T cells preferentially accumulate in intestinal tumors in an NKG2D-dependent manner and reveal a novel role for PD-1+ γδT cells in driving disease. We show that disease progression is associated with mild changes in the microbiota, but is independent of NKG2D expression. Lastly, we investigate the function of NKG2D in two models of intestinal inflammation and show that NKG2D is dispensable for the immune response in sterile colitis. Using a model of infectious-induced colitis, we show that NKG2D deficiency delays colonization of pathogenic bacteria, but does not influence the severity of inflammation.

Together, we provide valuable insight into NKG2D-mediated immunity in the setting of intestinal homeostasis, tumorigenesis and inflammation.