Interrogating unique DC adaptations to tissue to promote barrier immunity and tolerance

Project summary:
The immune system faces the external world and encounters pathogens, including viruses in barrier tissues (e.g.
skin, lung, and gut). There the immune system must detect and respond to pathogens, while simultaneously
preventing autoimmunity and promoting tissue repair. Dendritic cells (DC) in tissue are the key cells which
balance self-tolerance (preventing destruction of our bodies tissues) with pathogen surveillance.
The goal of this application is to understand how DCs develop uniquely and are adapted in the tissue to perform
and balance these functions. We have recently identified an important new mechanism, and a new molecular
target that dictates how DC in tissues differentiate in ways that impact their function. The goal of this proposal is
to gain a deeper understanding of DC biology along this regulatory axis, as a critical first step to intervene upon
tissue DC to restore health, when dysregulated. This would advance better immunization strategies as tissue
DCs are necessary for vaccine, viral, and cancer immunity. This application enables us to now test, for the first
time, how our myeloid compartment is architected to balance immune tolerance and pathogen surveillance in
barrier tissue sites.
Upon completion of this project we will understand how DCs in tissue are locally conditioned to behave in a site-
specific manner. We will gain an appreciation of how shared environmental sensing patterns are balanced
against individual cell identities, and tailored to specific pathogenic contexts. We will understand how local cues
modify the behavior of DCs, positioning us to test this in disease states. We will also identify DC behaviors that
are modifiable by local cues, enabling improved intervention on DC during disease pathogenesis and a better
model for successful DC development to improve adoptive cell therapy. The insights here are foundational, fill a
critical knowledge gap, and represent basic science advances needed to advance human health.

Grant Number: 5R01AR080436-04
NIH Institute/Center: NIH
Principal Investigator: Niroshana Anandasabapathy