Investigating the function of self-recognition receptors in tissue-resident natural killer cells

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Non-lymphoid organs, such as the liver, harbour a large population of innate immune cells, which are critical for immune protection, tissue repair, and normal organ physiology. The liver is constantly exposed to gut microbiota-derived antigens, therefore, maintaining immune tolerance is a challenge faced by immune cells in this organ. My research program focuses on understanding the mechanisms, which regulate innate immune cell functions, and aid in the maintenance of immune tolerance in non-lymphoid organs. Innate immune cells integrate signals from germ-line encoded receptors, such as members of the NKR-P1 receptor family to orchestrate complex immune responses. NKR-P1B is an inhibitory member of this receptor family, which recognizes genetically-linked C-type lectin-related Clr-b ligand, for self/non-self discrimination. We have detected NKR-P1B expression on subsets of innate lymphoid cells (ILC), including the natural killer (NK) cells, in different organs. Tissue-resident NK cells and ILC subsets make up a large proportion of innate immune cells in the liver. Understanding the role of NKR-P1B:Clr-b recognition on the biology of these cells, as well as, in liver immunity and immune tolerance, represents a basic science question underpinning normal immune cell functions in non-lymphoid organs. To this end, we have proposed the following aims: 1. Determine the precise molecular, phenotypic, and receptor expression profiles of liver-resident NK cell and ILC subsets. 2. Determine the role of NKR-P1B:Clrb recognition in liver-resident NK cell and ILC development and homeostasis. 3. Determine the role of NKR-P1B:Clrb recognition in liver-resident innate immune cell function. Using our NKR-P1B- and Clr-b-deficient mice, we will study receptor and ligand expression, tissue distribution, and dynamics of liver-resident NK cell and ILC populations by flow cytometry and confocal microscopy techniques to determine the role of NKR-P1B:Clr-b recognition in liver-resident NK cell and ILC development. We will also study the role of NKR-P1B:Clr-b recognition in liver-resident NK cell homeostasis, their interactions with liver Kupffer cells, effects of gut microbiota on receptor expression and function, and maintenance of immune tolerance. Finally, we will study the role of NKR-P1B:Clr-b recognition in the regulation of innate immune cell function, and immune tolerance in response to a virus challenge in the liver. This research program, and the proposed experiments using our gene knock-out mice, will explore the function of a unique and highly conserved immune receptor:ligand pair in tissue-resident innate immune cells to answer basic questions on how immune decisions, such as self/non-self recognition and immune tolerance, are facilitated. This study will teach us fundamental lessons about tissue-resident innate immune cell biology, and strengthen our understanding of immune cells in general.