Investigating the Role of the Microbiome in Mononuclear Phagocyte Function

Project Summary
Early life exposure to microbes is necessary for normal immune development, and clinical studies link
alterations in early life bacterial composition to subsequent development of inflammatory disorders such as
inflammatory bowel disease (IBD) and atopy such as asthma and dermatitis. In intestinal disease, microbiota-
specific T cells can drive tissue pathology. Therefore, it is crucial to understand the homeostatic mechanisms
that establish immune tolerance to commensal microbes during infancy in order to address inflammation in
adulthood. As antigen presenting cells (APCs) initiate the T-cell response, we want to elucidate how they respond
to microbes during early life. This work will have broad implications for development of therapies that address
the root of inflammatory disease including reshaping of pathogenic T cell responses.
The proposed project aims to describe how microbial colonization during early life drives the phenotype
and function of mononuclear phagocytes (MNP), which are a lineage of APCs known to coordinate host-microbe
responses. This lineage consists of monocytes that circulate in the blood, and the dendritic cells (DC) and
macrophages that they differentiate into upon entering tissue. While the factors that dictate this fate decision
remain undefined, these diverging cell fates lead to functionally different outcomes. DCs migrate to lymph nodes
to initiate T-cell responses while macrophages remain resident in the tissue to clear microbes and support barrier
function. Data from our lab shows that in early life but not adulthood, intestinal DCs expand and bring microbial
antigens to the thymus where they induce proliferation of microbe-specific T-cells. Interestingly in the early life
mesenteric lymph node, we see similar DC expansion and microbial trafficking but do not see the corresponding
T-cell response. This data led to our hypothesis that during early life, mononuclear phagocyte differentiation is
skewed towards a DC fate. We further hypothesize that early life lymphoid organs provide signals to instruct
microbial antigen processing and presentation resulting in life span and organ restriction of expansion of
microbiota recognizing T cells.
To address our hypothesis, in Aim 1 we will utilize single-cell RNA sequencing and adoptive monocyte
transfer to understand cell intrinsic and tissue regulation of monocyte fate over the lifespan. In Aim 2, by using
functional readouts, we will interrogate changes in DC function over the lifespan. Together, our work will reveal
how MNPs mediate T-cell responses to microbes during development, further advancing our ability to address
inflammation during adulthood.

Grant Number: 5F31AI181447-02
NIH Institute/Center: NIH
Principal Investigator: Amanda Chen