T helper (h) 17 cells are a newly described subset of CD4+ T cells which has been implicated, along with Th1 cells in the development of autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Regulatory T cells, on the other hand, protect from the development of autoimmunity. The mechanisms by which Th17 cells and factors associated with their differentiation promote autoimmunity have not been fully elucidated. We have previously determined that the differentiation of Th17 cells required the combined action of TGF-2 plus IL-6 and later IL-21. On the other hand IL-23 p19 is critical for sustaining Th17 responses and for the development of EAE since mice deficient for IL- 23 p19 are resistant to EAE. We found that IL-23 receptor (IL-23R), besides being expressed on Th17 cells, is also expressed on cells of the innate immune system such as macrophages and microglia. However, the role of IL-23 on non-T cells is to date unknown. We have generated a novel IL-23R green fluorescent protein (GFP) knockin (KI) reporter mouse in which all cells expressing the IL-23R will concomitantly express the GFP and become non responsive to IL-23. The IL-23R GFP KI mice will help us determine the relative contribution of IL- 23 on Th17 cells and macrophages/microglia in the development and progression of EAE. We have further determined that Th17 cells migrate quickly to the central nervous system (CNS) at the onset of EAE and their numbers correlate with the disease severity. However, the number of Th17 cells rapidly decline while the number of Th1 cells is maintained suggesting that Th17 cells may have a dominant role early on at the initiation phase and that Th1 cells are more involved during the chronic phase of EAE. We have generated an IL-17F RFP/DTR mouse in which Th17 cells can be deleted at any given time through the injection of diphtheria toxin and we will be able to determine the role of Th17 at different stages of the disease. Finally, in our efforts to further determine the mechanisms by which Th17 cells have enhanced pathogenic activity, we have isolated a surface molecule selectively expressed on Th17 cells named podoplanin. The expression of podoplanin has never been reported on T cells before but podoplanin has previously been implicated in the migration of tumor cells. Our preliminary data, injecting anti-podoplanin antibody in vivo in mice immunized with myelin antigen show an increase number of Th17 cells present in the CNS of the treated animals compared to control animals suggesting that podoplanin may play a role in the migration of Th17 cells.

Public Health Relevance

Based on our preliminary data and using novel reagents that we have generated, we have designed experiments to address several outstanding questions that are important for our understanding of autoimmune diseases: 1) Determine the interplay between effector Th17 and Th1 cells, and T-reg cells during EAE, 2) Determine the role of podoplanin in the development of Th17 cells 3) Determine how IL-23 exacerbate the development of EAE through its action on Th17 and cells of the innate immune system. Project Narrative These studies will complement ongoing studies on Th17 cells and regulatory T cells and contribute to our overall understanding of the mechanisms involved in the development of autoimmunity and their regulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Utz, Ursula
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Benaroya Research Institute at Virginia Mason
United States
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Glatigny, Simon; Duhen, Rebekka; Arbelaez, Carlos et al. (2015) Integrin alpha L controls the homing of regulatory T cells during CNS autoimmunity in the absence of integrin alpha 4. Sci Rep 5:7834
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
Peters, Anneli; Burkett, Patrick R; Sobel, Raymond A et al. (2015) Podoplanin negatively regulates CD4+ effector T cell responses. J Clin Invest 125:129-40
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Glatigny, Simon; Duhen, Rebekka; Oukka, Mohamed et al. (2011) Cutting edge: loss of ?4 integrin expression differentially affects the homing of Th1 and Th17 cells. J Immunol 187:6176-9
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Jager, Anneli; Dardalhon, Valerie; Sobel, Raymond A et al. (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183:7169-77
Elyaman, Wassim; Bradshaw, Elizabeth M; Uyttenhove, Catherine et al. (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106:12885-90
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