Control of Regulatory T Cell Function by Toll-Like Receptor 7

ABSTRACT
Regulatory T cells (Tregs) are critical for the maintenance of immunological tolerance but more recently their
importance in regulating other aspects of tissue homeostasis has been an area of intense interest. Most
relevant to this application are populations of tissue-resident Tregs that accumulate upon injury and facilitate
tissue repair by producing factors such as the EGF family member amphiregulin (Areg). These repair functions
are distinct from the suppressive function classically attributed to Tregs, but the signals that instruct Tregs to
adopt these distinct functional modalities have not been well defined. The IL-1 family cytokines IL-18 and IL-33
are involved at some level, at least in certain tissues, but it remains unclear whether these cytokines act as the
key initial determinants of Treg function.
This proposal will test the hypothesis that Toll-like receptor 7 (TLR7) signaling in Tregs is a key determinant of
Treg tissue repair function. We propose that TLR7 enables Tregs to sense pathogen-derived nucleic acids as
well as self RNA released from damaged host tissues. Our hypothesis is based on our analysis of a panel of
TLR reporter mice, which revealed that only TLR7 is expressed on Tregs, as well as strong preliminary data
demonstrating that TLR7 can induce expression of the signature tissue repair gene, Areg, in both murine and
human Tregs. Using newly generated mice with Treg-specific deletion of TLR7, we will examine the
importance of TLR7 signaling in Tregs during lung damage (Aim 1). Single-cell RNA sequencing will identify
which subsets of lung Tregs are controlled by TLR7 and will define TLR7-dependent genes in Tregs. We will
also investigate the importance of IL18R and IL33R signaling in Tregs, using mice with Treg-specific deletion
of these receptors, and will determine the extent to which TLR7, IL18R, and IL33R regulate distinct aspects of
Treg expansion and/or differentiation in response to diverse lung damaging agents (Aim 2). Finally, we will
build on our recent work that identified a mechanism by which the TLR chaperone Unc93b1 specifically
dampens TLR7 signaling. Using Tregs from mice with mutant Unc93b1 that have enhanced TLR7 signaling,
we will test whether adoptive therapy of Tregs with enhanced TLR7 responses to viral and self RNA can
mediate more effective repair of lung damage (Aim 3).
Altogether, these studies will define the signals that control Treg tissue repair functions and test the therapeutic
potential of amplifying these signals in the context of lung damage, a key first step toward therapeutic
manipulation of Treg function for clinical benefit.

Grant Number: 5R01AI158724-05
NIH Institute/Center: NIH
Principal Investigator: Gregory Barton