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.
The proposed research aims to establish the detailed migration programs of recently identified lymphocyte subsets in barrier tissues. The outcomes will enhance our understanding of how innate lymphocyte immunity is established to ward off pathogens in barrier tissues such as intestine. Moreover, the results are expected to provide novels strategies to regulate immunity and inflammation in barrier tissues.
|Kim, Myunghoo; Friesen, Leon; Park, Jeongho et al. (2018) Microbial metabolites, short-chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice. Eur J Immunol 48:1235-1247|
|Kim, Chang H (2018) Immune regulation by microbiome metabolites. Immunology 154:220-229|
|Kim, Chang H (2018) Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis. Immune Netw 18:e1|
|Hashimoto-Hill, Seika; Friesen, Leon; Park, Sungtae et al. (2018) RAR? supports the development of Langerhans cells and langerin-expressing conventional dendritic cells. Nat Commun 9:3896|
|Kim, Chang H (2018) Microbiota or short-chain fatty acids: which regulates diabetes? Cell Mol Immunol 15:88-91|
|Park, Jeongho; Lee, Jang-Won; Cooper, Scott C et al. (2017) Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response. J Leukoc Biol 102:1093-1102|
|Hashimoto-Hill, S; Friesen, L; Kim, M et al. (2017) Contraction of intestinal effector T cells by retinoic acid-induced purinergic receptor P2X7. Mucosal Immunol 10:912-923|
|Kim, Myunghoo; Kim, Chang H (2017) Regulation of humoral immunity by gut microbial products. Gut Microbes 8:392-399|
|Kim, Myunghoo; Kim, Chang H (2016) Colonization and effector functions of innate lymphoid cells in mucosal tissues. Microbes Infect 18:604-614|
|Kim, Myunghoo; Qie, Yaqing; Park, Jeongho et al. (2016) Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host Microbe 20:202-14|