Project 467241

The essential role of innate immunity, the bodys first line of defence, in pathogen clearance is reflected by its remarkable existence and diversity at every level of the evolutionary tree of life. Indeed, plants and invertebrates rely solely on their innate immune system to eliminate infectious agents. Similarly, innate immune responses in vertebrates are sufficient to eradicate pathogens. Our research group has focused on the memory capacity of innate immunity termed ;trained immunity. We have recently demonstrated that live vaccination (e.g. Bacille Calmette-Guérin) or adjuvant treatment (e.g. β-glucan) significantly increases hematopoietic stem cells (HSCs) via type II interferon (IFN) or interleukin (IL)-1 signaling, respectively. This results in complete epigenetic remodeling, notably through altered innate immune responses with profound protection against infections. Interestingly, innate lymphoid cells (ILCs) are distinguished from conventional T cells due to their lack of antigen-specific receptors and their rapid response to inflammatory cytokines. While key training cytokines (e.g. IFN or IL-1) were identified, their cellular sources are unknown. Therefore, in the current study, we hypothesize that β-glucan can directly train ILCs and ILCs are the major source of key cytokines involved in training HSCs. Here, we propose to investigate the role of ILCs in β-glucan-induced trained immunity in mice by using loss- and gain-of-function approaches. We will evaluate the impact of β-glucan on the development and function of ILCs and assess the impact of ILCs on HSC-mediated trained immunity. Insight into the mechanisms of these ;trained ILCs and ILC-trained HSCs will advance our understanding of their unique roles in generating innate memory responses.