Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) characterized by inflammation and demyelination of the CNS. Two subsets of CD4+ T cells, Th1 and Th17 cells, have been implicated in the pathogenicity of MS and EAE. The interactions between CD4+ T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) are necessary in both the periphery and central nervous system (CNS) to elicit autoimmunity. Clinical manifestations of EAE do not only require the initial priming of naive autoreactive CD4+ T cells in the peripheral immune system but critically depends on the reactivation of neuroantigen-specific CD4+ T cells within the CNS to develop into effector T cells. Dendritic cells are a heterogeneous class of professional antigen-presenting cells (APCs) capable of initiating, amplifying and regulating immune responses. During ongoing EAE and MS, a substantial accumulation of dendritic cells (DC) has been found in the CNS supporting their active participation in the pathophysiology of the diseases. Conventional DCs have been implicated in priming and the amplification of the pathogenic T cell response in EAE. On the other hand, another subset of dendritic cells, plasmatoid DC have been shown to have regulatory roles in the disease. Understanding the function and regulation of different subsets of dendritic cells is therefore important because these cells could serve as a means to regulate or exacerbate autoimmune responses in EAE and MS. Using a reporter mouse, which tracks retinoid-related orphan receptor-gt (RORgt)- expressing cells, we discovered a new population of dendritic cells characterized by the expression of RORgt, the transcription factor important for the development of Th17 cells. We did not detect these cells in the lymphoid organs or CNS of naive mice. However, we observed these new CD11c+ RORgt+ dendritic cells in the CNS of mice with active EAE. In this proposal, we will test the innovative hypothesis that this subset of RORgt+ CD11c+ dendritic cells (DCs) represents a unique subset of dendritic cells and is important for the development of EAE and the restimulation of pathogenic Th17 cells in the CNS. We will (1) characterize these RORgt + dendritic cells by flow cytometry, histology and RNA-seq, and (2) determine the function of RORgt+ DCs in EAE. The completion of these studies will provide novel insights on the role of a newly identified subset of dendritic cells that expresses RORgt in the induction and modulation of pathogenic T cell responses. Addressing these questions will significantly contribute to our understanding of the ontogeny of dendritic cells an important cell subset of the immune system and hopefully identify new strategies aimed at preventing the activation and entry of pathogenic cell in the CNS during autoimmunity.

Public Health Relevance

Dendritic cells play an important role in the generation, amplification, and regulation of the autoimmune response in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). The purpose of this project is to determine the characteristics of a novel subset of dendritic cells and determine their function in the development of EAE.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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Benaroya Research Institute at Virginia Mason
United States
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Glatigny, Simon; Wagner, Catriona A; Bettelli, Estelle (2016) Cutting Edge: Integrin ?4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis. J Immunol 196:3542-6
Arbelaez, Carlos A; Glatigny, Simon; Duhen, Rebekka et al. (2015) IL-7/IL-7 Receptor Signaling Differentially Affects Effector CD4+ T Cell Subsets Involved in Experimental Autoimmune Encephalomyelitis. J Immunol 195:1974-83