An official website of the United States government.

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

MICROBIOTA SPECIFIC T CELL SELECTION

Investigators
Bettini, Matthew
Institutions
Baylor College of Medicine
Start date
2018
End date
2023
Objective
Project SummaryOver the millennia humans have coevolved with a large number of microorganisms, collectively known as themicrobiota, which provide many key signals that aid in the development and proper functioning of the immunesystem. It is vital to human health that the immune system remains tolerant to the microbiota maintaining asymbiotic relationship. To limit pathological immune responses against the microbiota, immune tolerance to themicrobiota must be established early in life. A breakdown in tolerance to commensal microbes can result inchronic inflammatory disorders such as inflammatory bowel disease, asthma and dermatitis. Homeostasis withthe microbiota is achieved by generation of antigen specific regulatory T cells that develop in both the thymusand periphery. Exposure to the microbiota, especially during the neonatal period is thought to be critical for thisTreg induction. It has been found in humans as well as in animal models of disease, that compositionalchanges in the microbiota, also known as dysbiosis, correlate with increased susceptibility to subsequentinduction of inflammatory disease. Notably, changes early in life are thought to have the most significantimpact on disease susceptibility. In animal models, colonization with select intestinal microbes sensitizes todisease. It remains unclear how tolerance against the microbiota is achieved, and further, if the ability to inducetolerance to intestinal microbes is limited to a specific early life developmental window. Using a mouse modelwhose T cell receptor recognizes intestinal microbes, we find intestinal colonization with this microbe leads toselection of T cells specific for that organism. We hypothesize that intestinal antigen presenting cells (APCs)that encounter these organisms traffic to the thymus where they induce T cell selection. In Aim 1 of theproposed work, we will use in vivo models to define how introduction of specific microbes leads to alterations ofT cell populations. We will also define whether there are differential impacts on T cell development dependingon the developmental window of when microbial colonization occurs. We will further define if timing ofcolonization with select microbes promotes or limits development of inflammatory disease. In Aim 2 we willdefine how the microbe or microbial product travels from the intestine to the thymus. We will determine theintestinal cell population required for trafficking of this microbe as well as define transcriptional profiles thatallow for T cell selection. This will identify pathways that we will be able to manipulate to limit or rescue fromthe development of autoimmunity.
Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project source
View this project
Project number
1R01AI136963-01A1
Categories
Prevention and Control
Microbiological Standards and Guidelines