Multiple sclerosis (MS) is the leading cause of neurological disability in young adults. Both MS and its model experimental autoimmune encephalomyelitis (EAE) are autoimmune diseases in which pathogenic and regulatory T cells targeting the central nervous system (CNS) play a pivotal role. Dendritic cells (DCs) control CNS-specific T cells in vivo, but the pathways controlling DCs in MS and EAE are poorly characterized. We and others found that the transcription factor aryl hydrocarbon receptor (AHR) expressed in T cells controls effector and regulatory T cells (Teffs and Tregs). Some studies strongly suggest a role for AHR in the control of DCs, but little is known about the role o AHR expressed in DCs (defined as AHRDC) during autoimmunity. We found that AHRDC deletion increases Teffs and worsens EAE. AHRDC promotes CD39 expression in DCs, which limits the activation of the NLRP3 inflammasome. AHRDC also induces the production of IL-27, which promotes the differentiation of Tregs. Finally, AHRDC activation with nanoparticles (NPs) suppresses EAE. Based on these novel findings, we view AHRDC as a master regulator of the development of Teffs and Tregs. We hypothesize that AHRDC regulates the T-cell response by suppressing NLRP3 inflammasome activation and inducing IL-27 production. Thus, we propose to study the regulation of the autoimmune T-cell response by AHRDC, and its potential as a therapeutic target.
Our specific aims are:
Specific Aim 1 : Determine the effects of AHRDC on pathogenic Th1 and Th17 cells. We propose to: 1) Determine the effects of AHRDC on Th1 and Th17 cells, 2) Establish the molecular mechanisms by which AHRDC limits the activation of the NLRP3 inflammasome, and 3) Define AHRDC target genes and transcriptional pathways.
Specific Aim 2 : Establish the effects of AHRDC on Tr1 and FoxP3+ Tregs. We propose to: 1) Establish the induction of FoxP3- and FoxP3+ Tregs by AHRDC, 2) Analyze the molecular mechanisms by which AHRDC controls IL-27 expression, and 3) Define the role of AHRDC in the activation and polarization of T cells in healthy controls and MS patients.
Specific Aim 3 : Define the mechanisms by which NPs targeting AHRDC suppress EAE.
This aim evaluates the translational value of targeting AHRDC using novel NPs in pre-clinical models. We propose to 1) Define the molecular effects of NPs on DCs, 2) Establish the control of pathogenic and regulatory T cells by NPs and the mechanisms involved, 3) Evaluate the therapeutic effects of NPs in acute and chronic EAE models that recapitulate different aspects of human MS. IN SUMMARY, we use unique tools in mouse and human experimental systems to study a novel aspect of AHR: its role in DCs as a master regulator of the autoimmune T-cell response. These studies will guide AHR- targeted therapies for inflammatory disorders, for example using the new NPs described in this project.
Autoimmune diseases are caused by the uncontrolled activity of the immune system. This project proposes to use in vitro and in vivo experimental systems to study the molecular mechanisms through which the aryl hydrocarbon receptor controls the immune response and to identify potential targets for therapeutic intervention in immune-mediated diseases.
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