This application proposes to continue study the immune factors that are important for the pathogenesis of newly characterized Th17 autoreactive T cells. In the previous funding period, we have made significant progress in investigating the mechanisms by which pathogenic Th17 (IL-17+) and Th1 (IFN-y+) autoreactive T cells cause autoimmune disease, and in studying whether the regulation of the pathogenic Th17 response differs from that of the Th1 response. Our studies demonstrated that increased Th17 responses rely on an enhanced d T cell response, raising the question whether manipulation of ?? T cell activation can prevent undesired Th17 responses. In studying factors that lead to ?? T cell activation, we found that adenosine is an important factor in tipping Th1 and Th17 autoreactive T cell generation in autoimmune uveitis (EAU). Adenosine significantly enhances Th17 responses via a pathway in which it enhances ?? T cell activation. Our preliminary results also showed that ?? T cells express greatly increased numbers of type A2 adenosine receptors (A2ARs) after activation and that this allows them to bind large amounts of adenosine; moreover, activated ?? T cells express decreased amounts of ecto-5'-nucleotidase (CD73), an enzyme critically involved in the generation of extracellular adenosine. The hypothesis of this application is that the dual effects of removal of adenosine by activated ?? T cells and the decreased ability of activated ?? T cells to express CD73, which decreases their ability to convert immunostimulatory ATP/AMP to immunosuppressive adenosine, lead to enhanced Th17 responses and autoimmune disease. We will exploit available knockout mice lacking A2ARs and determine whether the proinflammatory effect of ?? T cells on the Th17 response is limited if their ability to bind adenosine is reduced, whether selective A2AR agonists/antagonists can effectively manipulate Th17 responses, whether manipulation of the enzymatic function of CD73 is effective in controlling the Th17 response, and whether adenosine degradation enzyme (ADA) and ADA inhibitors are effective in manipulation of the regulatory activity of ?? T cells and thus Th17 response. The proposed studies will elucidate the molecular and cellular mechanism by which adenosine regulated autoimmune Th1 and Th17 responses. The continuation of this study and the clarification of the pathogenic role of, and relationship between, IFN-y+ and IL-17+ autoreactive T cells in EAU should contribute to our understanding of the mechanism of autoimmune disease pathogenesis.

Public Health Relevance

Uveitis is a sight-threatening, inflammatory disease. Mice can be induced for similar disease, either by immunization of the animals with a pathogenic antigen or by adoptive transfer with uveitogenic T cells. These experimental models have been extensively used for determination of the pathogenic mechanisms that is not possible to be directly approached in humans. Our laboratory has been engaged in the study of autoimmune pathogenesis for years. Our expertise in the characterization of pathogenic T cells, and in determination the mechanism causing an aberrant immune response should contribute to a better understanding of the disease pathogenesis of this newly identified Th17 pathogenic T cells in autoimmune diseases, that is much-need for the improvement of currently available therapeutic treatments.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
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Doheny Eye Institute
Los Angeles
United States
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Liang, Dongchun; Woo, Jeong-Im; Shao, Hui et al. (2018) Ability of ?? T cells to modulate the Foxp3 T cell response is dependent on adenosine. PLoS One 13:e0197189
Yun, Juan; Xiao, Tong; Zhou, Lei et al. (2018) Local S100A8 Levels Correlate With Recurrence of Experimental Autoimmune Uveitis and Promote Pathogenic T Cell Activity. Invest Ophthalmol Vis Sci 59:1332-1342
Yun, Juan; Jiang, Guomin; Wang, Yunsong et al. (2017) The HMGB1-CXCL12 Complex Promotes Inflammatory Cell Infiltration in Uveitogenic T Cell-Induced Chronic Experimental Autoimmune Uveitis. Front Immunol 8:142
Zhao, Zhenyang; Liang, Yuejin; Liu, Yin et al. (2017) Choroidal ?? T cells in protection against retinal pigment epithelium and retinal injury. FASEB J 31:4903-4916
Liang, Dongchun; Nian, Hong; Shao, Hui et al. (2017) Functional Conversion and Dominance of ?? T Subset in Mouse Experimental Autoimmune Uveitis. J Immunol 198:1429-1438
Zhao, Ronglan; Liang, Dongchun; Sun, Deming (2016) Blockade of Extracellular ATP Effect by Oxidized ATP Effectively Mitigated Induced Mouse Experimental Autoimmune Uveitis (EAU). PLoS One 11:e0155953
Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan et al. (2016) CD73 Expressed on ?? T Cells Shapes Their Regulatory Effect in Experimental Autoimmune Uveitis. PLoS One 11:e0150078
Li, Xue; Lu, Xiaoxiao; Sun, Deming et al. (2016) Adipose-Derived Mesenchymal Stem Cells Reduce Lymphocytic Infiltration in a Rabbit Model of Induced Autoimmune Dacryoadenitis. Invest Ophthalmol Vis Sci 57:5161-5170
Xiao, Qing; Li, Xue; Sun, Deming et al. (2016) TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK. J Immunol 197:3820-3830
Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan et al. (2016) Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis. J Immunol 196:2646-54

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