R01AI187465

Epigenetic checkpoint regulation of naive T-cell quiescence and peripheral tolerance - Epigenetic checkpoint regulation of naive T-cell quiescence and peripheral tolerance.

Maintaining the quiescence of autoreactive naïve T cells and preventing them from reacting to self-antigens are crucial for T-cell peripheral tolerance, contributing to immune homeostasis and suppression of autoimmune diseases.

We seek to understand how this process is regulated by T-cell-extrinsic and -intrinsic mechanisms.

The former includes regulatory-T-cell-mediated immunosuppression, and the latter covers checkpoint regulators of conventional naïve T-cell activation and effector differentiation.

These cell-intrinsic negative mechanisms remain to be fully explored, given that causes of numerous autoimmune disorders are still elusive, despite significant progress in our understanding of regulatory T cells and the final effector stage of inflammation and damage.

Immunogenetic studies suggest that environmental factors, such as nutrients, significantly impact the immune system.

However, how T-cell homeostasis and immune tolerance are programmed by nutritional cues is not well defined.

Although routinely considered permissive factors, they can profoundly affect T-cell metabolism, signal transduction, and gene regulation, raising questions about how they shape T-cell peripheral tolerance.

To explore this, we searched for cell-intrinsic checkpoint regulators of conventional T-cell reactivity to self-antigens.

This led to the discovery of the ascorbate transporter SLC23A2 as a negative regulator of the activation and effector differentiation of naïve T cells, independent of regulatory T cells.

We confirmed that SLC23A2 contributes to high levels of T-cell ascorbate.

Although ascorbate plays several biochemical roles, we propose its activity via TET methylcytosine dioxygenases (or DNA demethylases) in maintaining naïve T-cell quiescence and restricting activation and differentiation to effector T cells.

We also observed reduced ascorbate and increased DNA methylation in naïve T cells from aged animals and humans, suggesting this axis prevents spontaneous T-cell activation and effector differentiation during aging that cause inflammaging.

We plan to test the hypothesis that the ascorbate-TET axis acts as a checkpoint regulator, restricting the activation and effector differentiation of autoreactive naïve T cells in response to self-antigen stimulation.

We will approach this from several angles.

First, we will determine how ascorbate deficiency in T cells causes low-grade chronic autoimmunity, akin to inflammaging.

Then, we will establish the role of the ascorbate-TET axis in regulating T-cell activation and effector differentiation.

Finally, we will unveil how the ascorbate-TET axis acts stepwise to suppress naïve T-cell activation and differentiation into effector T cells upon TCR stimulation.

Successful completion of our study will reveal a crucial nutrient-epigenetic axis involving cell-intrinsic ascorbate and TET-DNA demethylation in maintaining naïve T-cell quiescence and peripheral tolerance, particularly in suppressing T-cell inflammaging-like autoimmunity.

The mechanistic insights gained in this project could enhance the diagnosis, prevention, or treatment of autoimmune diseases, especially during aging.

St. Jude Children's Research Hospital

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]

Memphis, Tennessee 38105 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)