# Role of AHR in Dendritic Cells in the Control of CNS Autoimmunity

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $372,171

## Abstract

PROJECT SUMMARY
 Effector and regulatory T cells targeting the central nervous system (CNS) play a pivotal role in the
pathogenesis of multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE).
Dendritic cells (DCs) control CNS-specific T cells, but the pathways regulating DC function are poorly
characterized. Published studies suggest a role for the ligand-activated transcription factor aryl hydrocarbon
receptor (AHR) in the control of DCs. During the previous grant cycle we have made the following findings: 1)
Deletion of AHR expressed in classical DCs (AHRcDC) worsens EAE and exacerbates autoimmune T-cell
responses, 2) Single-cell RNA-seq analyses of mouse and human classical DCs (cDCs) detected the
coordinated expression of AHR with the transcription factor KLF4 and the ectoenzyme CD39, 3) Indeed, AHRcDC
drives the expression of KLF4 in cDCs (KLF4cDC), a transcription factor known to limit NF-kB activation and drive
anti-inflammatory gene expression in macrophages, 4) KLF4cDC deletion worsens EAE and exacerbates
pathogenic T-cell responses, 5) AHRcDC also drives the expression of CD39 in cDCs (CD39cDC), which degrades
pro-inflammatory extracellular ATP (eATP) and participates in the synthesis of anti-inflammatory adenosine, 5)
CD39cDC deletion worsens EAE and exacerbates pathogenic T-cell responses, 6) AHR activation induces mouse
and human tolerogenic cDCs, and 7) A novel probiotic engineered to produce the AHR agonist IAA (named
EcNIAA) suppresses EAE in an AHRcDC-dependent manner. Based on these findings we hypothesize that
AHRcDC-driven KLF4 and CD39 expression in cDCs limits CNS autoimmunity. Our specific aims are:
Specific Aim 1: DETERMINE THE ROLE OF KLF4 IN THE CONTROL OF cDCS BY AHRcDC.
We propose to: 1) Define KLF4-dependent and KLF4-independent transcriptional programs controlled by AHRcDC
in single cell and bulk genomic studies, and 2) Establish the role of KLF4 in the control of NF-kB by AHR in cDCs.
Specific Aim 2: ESTABLISH THE ROLE OF CD39 IN THE CONTROL OF T CELLS BY AHRcDC.
We propose to: 1) Define the effects of AHRcDC-induced CD39cDC expression on myelin-specific T cells, 2)
Determine whether the AHRcDC-CD39cDC axis promotes regulatory T cell differentiation, and 3) Establish the roles
of AHRcDC, KLF4cDC and CD39cDC in the control of T cells by DCs in healthy controls and MS patients.
Specific Aim 3: DEFINE THE ROLE OF AHRcDC IN EAE SUPPRESSION BY EcNIAA.
This aim evaluates the therapeutic potential of activating AHRcDC with EcNIAA, a novel probiotic engineered to
produce the AHR agonist IAA. We propose to: 1) Evaluate the therapeutic effects of EcNIAA in EAE, 2) Define
the roles of AHRcDC and KLF4cDC on the transcriptional modulation of DCs by EcNIAA, 3) Establish the contribution
of AHRcDC and CD39cDC to the control of effector and regulatory T cells by EcNIAA.
IN SUMMARY, in this competitive renewal we use unique tools and clinical samples to study a novel aspect of
AHRcDC as a regulator of T...

## Key facts

- **NIH application ID:** 10752679
- **Project number:** 5R01ES025530-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Francisco J. Quintana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,171
- **Award type:** 5
- **Project period:** 2016-06-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752679

## Citation

> US National Institutes of Health, RePORTER application 10752679, Role of AHR in Dendritic Cells in the Control of CNS Autoimmunity (5R01ES025530-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10752679. Licensed CC0.

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