In vivo function of the immunoreceptor NKG2D in intestinal inflammation and tumorigenesis

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.Open Acces

Age Affects the Expression of Maternal Care and Subsequent Behavioural Development of Offspring in a Precocial Bird

Variations of breeding success with age have been studied largely in iteroparous species and particularly in birds: survival of offspring increases with parental age until senescence. Nevertheless, these results are from observations of free-living individuals and therefore, it remains impossible to determine whether these variations result from parental investment or efficiency or both, and whether these variations occur during the prenatal or the postnatal stage or during both. Our study aimed first, to determine whether age had an impact on the expression of maternal breeding care by comparing inexperienced female birds of two different ages, and second, to define how these potential differences impact chicks’ growth and behavioural development. We made 22 2-month-old and 22 8-month-old female Japanese quail foster 1-day-old chicks. We observed their maternal behaviour until the chicks were 11 days old and then tested these chicks after separation from their mothers. Several behavioural tests estimated their fearfulness and their sociality. We observed first that a longer induction was required for young females to express maternal behaviour. Subsequently as many young females as elder females expressed maternal behaviour, but young females warmed chicks less, expressed less covering postures and rejected their chicks more. Chicks brooded by elder females presented higher growth rates and more fearfulness and sociality. Our results reveal that maternal investment increased with age independently of maternal experience, suggesting modification of hormone levels implied in maternal behaviour. Isolated effects of maternal experience should now be assessed in females of the same age. In addition, our results show, for first time in birds, that variations in maternal care directly induce important differences in the behavioural development of chicks. Finally, our results confirm that Japanese quail remains a great laboratory model of avian maternal behaviour and that the way we sample maternal behaviour is highly productive

A summary of current NKG2D-based CAR clinical trials

Summary Cancer immunotherapies have significantly improved patient survival and treatment options in recent years. Nonetheless, the success of immunotherapy is limited to certain cancer types and specific subgroups of patients, making the development of new therapeutic approaches a topic of ongoing research. Chimeric antigen receptor (CAR) cells are engineered immune cells that are programmed to specifically eliminate cancer cells. Ideally, a CAR recognizes antigens that are restricted to tumor cells to avoid off-target effects. NKG2D is an activating immunoreceptor and an important player in anti-tumor immunity due to its ability to recognize tumor cells and initiate an anti-tumor immune response. Ligands for NKG2D are expressed on malignant or stressed cells and typically absent from healthy tissue, making it a promising CAR candidate. Here, we provide a summary of past and ongoing NKG2D-based CAR clinical trials and comment on potential pitfalls

NKG2D signaling regulates IL-17A-producing γδT cells in mice to promote cancer progression

γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance, homeostasis and cancer. γδT cells recognize stressed cells or cancer cells through the NKG2D receptor to kill these cells and maintain normality. Contrary to the well-established anti-tumor function of these NKG2D-expressing γδT cells, we show here that, in mice, NKG2D regulates a population of pro-tumor γδT cells capable of producing IL-17A. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduced the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increased the frequency of γδT cells. Together, these data support the hypothesis that in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A