Early life regulation of microbiota specific thymic T cell development

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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.