# Remodeling of Lymph Node-Derived Cytokine Responses at the Infected Tissue Site

> **NIH NIH R37** · CORNELL UNIVERSITY · 2024 · $465,973

## Abstract

Project Summary / Abstract
The immune system has the powerful ability to swiftly mobilize in response to challenge, migrating between and
within tissues to locally deliver inflammatory mediators that can be anti-microbial, anti-tumor or auto destructive.
Most infected/inflamed tissues express elevated levels of many chemokines and most chemokine receptors
(CRs) can bind to multiple ligands, creating a highly redundant network of signals. The optimization of immune
cell navigation through such a complex microenvironment remains unclear. Indeed, current immunotherapies for
various cancers have exposed deficiencies in our understanding of how effector T cells (Te) access and position
themselves in inflamed tissues, with very inefficient recruitment/retention of CAR T cells into the tumor itself.
Such microanatomical positioning driven by CRs and chemoattractants exposes Te to regional antigen and
inflammatory signals that likely tune transcriptional programs to boost or restrain effector functions. Indeed,
single cell transcriptomics analyses in infected and malignant tissues point to significant functional heterogeneity
in tissue Te cells, but lack spatial and temporal information that shape such heterogeneity. We have used an
optogenetic strategy to “timestamp” Th1 cells within inflamed tissues and have found an unexpected change in
CR expression based on time from tissue entry. This proposal aims to gain new knowledge of the temporal use
of CRs that impact Th1 functional (re)programing. Such insight would enable design of targeted therapeutic
approaches that harness or manipulate Te within the target tissues of infection, inflammation or malignancy.
We have utilized in vivo optogenetic approaches combined with RNAseq to follow changes in CR expression by
Te in the inflamed skin. Our data reveal a striking temporal regulation of CR transcription by Th1 cells following
tissue entry. Disruption of this sequence of CR expression comprises Th1 function. We hypothesize that CR
gene expression modulated in a temporal fashion enables incoming effector T cells to differentially
sense chemotactic cues for correct tissue positioning. Moreover, location-specific events of tissue
entry, early activation, through to positioning at the infection foci transmit distinct signals that hone the
Th1 transcriptional program to optimize effector function. Tested in the following aims:
Specific Aim 1. Signals that dynamically regulate CR expression and Th1 intra-tissue programing.
Specific Aim 2. Stage-specific CR requirements.
Specific Aim 3. Biological impact of temporal regulation of CR expression.

## Key facts

- **NIH application ID:** 10862752
- **Project number:** 5R37AI072690-13
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Deborah J Fowell
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,973
- **Award type:** 5
- **Project period:** 2008-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862752

## Citation

> US National Institutes of Health, RePORTER application 10862752, Remodeling of Lymph Node-Derived Cytokine Responses at the Infected Tissue Site (5R37AI072690-13). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10862752. Licensed CC0.

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