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

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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-cell autoimmunity, and its potential as a therapeutic target in autoimmune diseases.