Homing of Functionally Distinct ILC Subsets

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 DESCRIPTION (provided by applicant): Optimal immune responses to pathogens in barrier tissues require timely regulation of lymphocyte recruitment to lymphoid tissues and effector sites. Innate lymphoid cells (ILCs) are cells of the lymphoid lineage and are enriched in mucosal tissues. They play important roles in fighting pathogens, inducing lymphoid tissue development and strengthening epithelial barrier function. ILCs are sub-divided into three major subsets with distinct effector cytokine phenotype: ILC1 produce the Th1 cytokine IFN-, ILC2 produce Th2 cytokines, and ILC3 produce Th17 cytokines. A major problem in the field is our lack of understanding of the migration program of ILC subsets. While ILCs are enriched in barrier tissues and distributed in a tissue-specific manner, we currently don't understand how ILCs migrate to these tissues for development and effector function. Our preliminary data raised the possibility that ILCs have highly sophisticated migration programs that support their development and effector function. Particularly, the data suggest that certain homing receptors regulate tissue-specific population, migration, and function of ILC subsets. We hypothesize that ILC subsets undergo potentially distinct homing receptor switches to migrate from the generative sites to lymphoid tissues and then to effector sites. Moreover, these homing receptor switches are likely to be regulated at multiple stages of ILC development in the bone marrow and periphery by cytokines and tissue factors. To test the hypothesis and obtain detailed information regarding ILC migration, we devised the following three specific aims: Aim 1. Determine the shared and differential migration programs of ILC subsets. Aim 2. Determine the roles of HRs in ILC migration and tissue tropism. Aim 3. Determine the impact of HRs on effector functions of ILC subsets. The project will generate fundamental knowledge on ILC migration and distribution in the body with a special emphasis on ILC subset-specific trafficking. Homing receptors important for ILC effector function and the factors that regulate the expression of these receptors will be identified. The outcomes will provide novel insights into the establishment of ILC immunity in barrier tissues.