Early life regulation of microbiota specific thymic T cell development

Project Summary
Early life exposure to environments rich in microbial products corresponds with a more diverse microbiota and
significantly decreases susceptibility to developing asthma and atopic sensitization. However, it is unclear how
this early life exposure supports proper immune function. In recently published data, we find thymic expansion
of microbiota specific T cells in early life. This is driven by microbiota carrying intestinal dendritic cells migration
from the intestine to the thymus. We hypothesize specific microbial signals in intestinal environment in young
mice, including signaling downstream of microbe attachment to intestinal epithelial cells, encourages intestinal
DC trafficking to thymus. In the thymus, we hypothesize these microbes serve as a template to ensure expansion
of microbe specific T cells, offering protection from pathogen challenge. Understanding these specific microbial
derived signals, as well as unique thymic environmental cues during early life will allow us to understand this
novel pathway. In Aim 1 of the proposed work, we will use in vivo models to understand the role for the intestine
in this system, identifying molecular signals activating thymic migration of intestinal DCs. In Aim 2 we will
determine the thymic signals that allow for thymic expansion of microbiota specific T cell. We will determine
whether gut migratory APCs regulate selection or expansion of microbiota specific T cells. Finally, will determine
whether migration is restricted by the age of the thymus or intestine environment through a series of thymic
transplant studies. These mechanistic studies will help identify pathways that we will be able to manipulate to
alter thymic T cell development and limit or rescue from the development of inflammatory disease.

Grant Number: 5R01AI173406-03
NIH Institute/Center: NIH
Principal Investigator: Matthew Bettini