U01AI168640

Parsing Cholesterol Metabolite Regulation of Skin Immunocytes in Children to Identify Archetypes of Human Neonatal Immune System - Project Summary

The Type 3 cytokine (IL-17 and IL-22) producing lymphocytes (T3L) are strategically located at the mucocutaneous barrier tissues and serve as sentinels of tissue perturbations at the interface with the outside world.

Skin resident T3L develop in early life and perform dual function: in early life, they promote tissue fitness by interacting with commensals to produce tonic IL-17; and throughout life, they defend against pathogens by rapid secretion of IL-17 essential for recruitment of neutrophils to inflamed tissues and fortifying the barrier tissues.

Commensal dysbiosis by low dose antibiotics during early life of animals (E15 for mice and 24-28 weeks of gestation in humans) can lead to aberrant IL-17 production and is linked to metabolic dysfunctions observed in adults, including obesity.

We discovered recently that a subset of T3L in mice can sense the dietary cholesterol metabolites oxysterols to calibrate their function. These cells arise immediately after birth in mice and they are the fastest (innate-like) lymphoid responders to tissue perturbations.

The recognition of oxysterols by T3L is mediated by the G protein-coupled receptor GPR183, which is expressed by all T3L in mice and humans. GPR183 has been genetically linked to psoriasis, colitis, and type 1 diabetes susceptibility in humans.

In mice, early life skin T3L subset mediates IL-17-driven psoriatic responses downstream of toll-like receptor signaling in keratinocytes. This function is diet-modulated and dependent on GPR183, with high cholesterol diet leading to severe diseases, and conversely, vegetarian diet dampening IL-17 production and dramatically moderating disease severity.

This discovery is the first to identify potential sensors of immune modulatory dietary metabolites on lymphocytes outside the gut.

In humans, T3L are known to be important in psoriasis in adults, but almost nothing is known about them in early life immune system. This gap in knowledge in large part exists because there is no systematic census of T3L and their interacting partners in mucocutaneous tissues of children.

This proposal will fill this gap using innovative, unbiased, complementary single cell interrogation methods to catalogue all immune cell types and states in the skin of children from infancy to adulthood, stratified multi-parametrically, including BMI, dietary habits, and infection history.

The skin cell atlas of children will be instrumental in establishing correlation between dietary habits and propensity towards hyper-inflammatory responses, modulated by skin-resident T3L.

The genome-wide information rich map will identify gene networks that govern intercellular communications and cell lineage diversification, setting a major precedent of tissue immune systems relevant for childhood immunity, and accelerate progress towards defining mechanisms of early life immune system development.

University Of Massachusetts Medical School

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Worcester, Massachusetts 01655 United States

Single Zip Code

Immune Development in Early Life (IDEaL) (U01 Clinical Trial Not Allowed) (RFA-AI-20-077)

Amendment Since initial award the total obligations have increased 297% from $816,899 to $3,243,089.