Investigating a RORgt-expressing antigen presenting cell required for peripheral Treg responses to gut microbiota

Abstract
The human intestine retains countless microbes, existing in a mutualistic relationship with the host by providing
nutrients and other metabolites necessary for overall well-being. Developing tolerance or inflammation to the
countless commensal microbes within the gut is dependent on antigen presenting cells (APCs) and their
interactions with naïve T cells. Thus, understanding how heterogeneous populations of APCs modulate immune
responses within the gut in response to gut microbiota provides potential avenues to developing strategies to
mitigate inflammatory diseases of the intestine such as inflammatory bowel disease (IBD) while also adding to
our understanding of commensal immunity. The goal of this project is to investigate a newly discovered, distinct
antigen presenting cell expressing RORgt, a nuclear transcription factor not classically associated with antigen
presentation, within the gut. This RORgt+ APC has been shown by our group and others to be required for the
generation of gut microbe-specific induced Tregs (pTregs), thereby maintaining intestinal homeostasis. However,
while there is consensus in the field regarding the existence of a new RORgt+ APC required for the generation
of pTregs to microflora, there is great debate as to the definitive identity and behavior of this population. Various
groups have proposed different candidates of RORgt-expressing APCs as the essential population coordinating
peripheral Treg responses to gut microbiota. This project aims to not only shed light on the blurred lines among
the various subsets of RORgt-expressing APCs, but also to examine the nature of these cells, specifically where
these APCs reside in the gut, what their behavior is within the intestinal microenvironment, and which cell types
they interact with, both in homeostatic and pathogenic conditions. These objectives will be addressed by using
a combination of intricate transgenic mouse manipulation, deep multi-omic analysis of fate-mapped RORgt+
APCs in different tissues and perturbations, and advanced microscopy techniques, including high-resolution
multiplexed, volumetric imaging and intravital microscopy. This research will further our understanding of the
mechanisms by which tolerance is established towards the expansive microbial ecology residing within the gut.
Through these results, targeted therapies can be developed to promote commensal tolerance within the gut and
alleviate inflammatory symptoms commonly observed in autoimmune disorders such as inflammatory bowel
disease.

Grant Number: 5F32AI181496-02
NIH Institute/Center: NIH
Principal Investigator: Francis Chen