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Principal Investigator: Joonsoo Kang
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2024
Award: $707,833
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Immunological control of mucosal barrier development and maintenance is a critical process, as imbalances in
immune sentinel activity can lead to skin, lung and gut inflammatory diseases. Central in the mucosal tissue
homeostasis are type 3 cytokine producing lymphocytes. Cytokines, cytokines receptors and master
transcriptions involved in tissue development and barrier fortification have been identified based on analyses of
loss of function models in human and mice. However, non-inflammatory factors that orchestrate the type 3
responses in tissues to assure proper immune reactions and prevent aberrant inflammation have not been well
characterized.
We discovered that oxysterols, a major class of cholesterol metabolites with established immunomodulatory
activities, are the primary positional cues for the stereotypical type 3 lymphocytes in the skin called Tγδ17 cells.
Ebi2 (encoded by Gpr183) is the G protein coupled receptor (GPCR) that senses specific types of oxysterols,
and is expressed on all type 3 cytokine producing lymphocytes. Increased dietary cholesterol enhances Tgd17
activity at the skin interface via augmented oxysterol production and sensing. However, how tissue resident cells
contribute to the anatomical framework that generate the final positional cues for dermal IL-17 secreting innate
T lymphocytes is not known. Moreover, whether oxysterols are involved in the development of skin-tropic Tgd17
and other type 3 cytokine producing lymphocytes is not known.
In this project we will test the hypothesis that Tgd17 cells maintain barrier tissue homeostasis by sensing cues
that reflect nutritional states and inputs from the peripheral nerve system. Metabolic changes in the epithelial-
neuronal niche in the skin control optimal microanatomical Tgd17 positioning and function via GPR183. This
integrated sensory mechanism for cholesterol metabolism and neuronal inputs is imprinted early in Tγδ17
thymocyte maturation through interactions with a novel subset of thymic epithelial cells programmed to produce
oxysterols. The conceptual basis of this project is innovative as there are no precedents for the oxysterol-
regulated mucosal tissue hub integrating epithelial-neuronal-immune communications critical for barrier tissue
fitness.
Terms: <25-HC 7alpha-hydroxylase><25-hydroxycholesterol><25-hydroxycholesterol 7-alpha-hydroxylase><25-hydroxycholesterol 7alpha-hydroxylase><3 beta-hydroxysteroid 7-alpha-hydroxylase><5 alpha-androstane 3 beta,17 beta-diol 7 alpha-hydroxylase><5alpha-androstane-3beta,17beta-diol 7-alpha-hydroxylase><Acute><Anatomic Sites><Anatomic structures><Anatomy><Arthritis><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Autoimmune Diseases><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding Proteins><Biochemical><Birth><Body Tissues><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><CYP7B1><Cell Body><Cell Communication><Cell Function><Cell Growth and Maintenance><Cell Interaction><Cell Maintenance><Cell Physiology><Cell Process><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cholesterol><Cholesterol Homeostasis><Communication><Corium><Cues><Cutaneous><Cutaneous Disorder><Cutis><Cytokine Receptors><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><DHEA 7-alpha-hydroxylase><Data><Dermal><Dermatoses><Dermis><Development><Diet><Diet Modification><Dietary Cholesterol><Dietary Fats><Dietary Modifications><Disease><Disorder><Disseminated Neurodermatitis><EVI16><Ecotropic Viral Integration Site 16><Eczema><Eczematous Dermatitis><Ensure><Enzyme Gene><Enzymes><Epidermis><Epithelial Cells><Epithelium><Fats><Fatty acid glycerol esters><Food><Fortification><Funding><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Gamma-delta T cells><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genetic Transcription><Gestation><Glia><Glial Cells><High Fat Diet><Homeostasis><Homing><Human><Hydroxylases><Hyperactivity><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-22><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune reaction><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunomodulation><Impairment><Incidence><Infection><Infectious Skin Diseases><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Response><Intake><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Intervention><Intervention Strategies><Knowledge><Kolliker's reticulum><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Link><Lung><Lung Respiratory System><Lymphatic cell><Lymphocyte><Lymphocytic><Lymphoid Cell><Maintenance><Maps><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Microanatomy><Microscopic Anatomy><Mixed Function Oxidases><Mixed Function Oxygenases><Modeling><Modern Man><Molecular><Monooxygenases><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurilemma Cell><Neurilemmal Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurons><Nociceptors><Non-neuronal cell><Nonneuronal cell><Nutritional><Obesity><Pain><Painful><Parturition><Pathway interactions><Pattern><Peripheral Nerves><Physiological Homeostasis><Position><Positioning Attribute><Pregnancy><Probability><Process><Production><Protein Binding><Psoriasis><RNA Expression><Regulation><Reporter><Response Elements><Rest><SOX4><SOX4 gene><SRY-Box 4><SRY-Related HMG-Box Gene 4><Schwann Cells><Sentinel><Severities><Shapes><Skin><Skin Diseases><Skin Diseases and Manifestations><Skin development><Specific qualifier value><Specificity><Specified><Sterols><Stromal Cells><Subcellular Process><System><T-Cells><T-Lymphocyte><Testing><Thesaurismosis><Thymic epithelial cell><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><adiposity><allergic dermatitis><allergic eczema><arthritic><autoimmune condition><autoimmune disorder><autoimmunity disease><bound protein><cell type><cholest-5-ene-3 beta,25-diol><cholesterol metabolism><chronic inflammatory skin><commensal bacteria><commensal bacterial species><corpulence><cutaneous barrier><cutaneous disease><cutaneous infection><cytochrome P-450 CYP7B1><cytokine><dehydroepiandrosterone 7-alpha-hydroxylase><dermal barrier><dermal disease><dermal disorder><developmental><diet alteration><dietary><dietary alteration><dietary lipid><diets><eczematous><epidermal barrier><fitness><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoreaction><immunoregulation><immunoregulatory><imprint><infected skin><inflammatory disease of the intestine><inflammatory disorder of the intestine><innovate><innovation><innovative><insight><interleukin-22><interventional strategy><intestinal autoinflammation><keratinocyte><loss of function><lymph cell><metabolism disorder><mouse model><murine model><nerve cement><neuronal><nociceptive neurons><non-genetic><nongenetic><novel><nutritious><oxysterol 7-alpha-hydroxylase><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><pathogen><pathway><prevent><preventing><psoriasiform><psoriatic><pulmonary><response><sensor><sensory integration><sensory mechanism><skin barrier><skin disorder><skin infection><skin organogenesis><thymocyte><thymus derived lymphocyte><trait><transcription factor><western diet><western-style diet><western-type diet><γδ T cells><γδT cells>