Over the past two decades, studies on pathogenic T cells have been guided by the dogma that these are mostly CD4+ Th1-type T cells and produce interferon-? (IFN-?). This concept has been revised recently because of studies showing that induction of many autoimmune diseases is not abolished in the absence of Th1 cells and that autoreactive T cells producing IL-17, but not IFN-?, play an important role in autoimmune diseases. Our preliminary studies determining the role of IL-17+ autoreactive T cells in EAU have shown that IL-17-expressing T cells can be readily identified in EAU-susceptible mice and that both IFN-? + and IL-17+ IRBP-specific T cells are uveitogenic. The observation that growth factors required for activation of IFN-?+ and IL-17+ IRBP-specific T cells IRBP-specific T cells are different and that ?? T cells play a major role in the activation of IL-17+ cells, but that they are not as important for IFN-? response, prompts us to place our emphasis on determining whether dominance of one type of pathogenic T cell is determined by the immune conditions under which T cells become activated. We will determine the activation requirements of IFN-? + and IL-17+ IRBP-specific T cells in the periphery and inside the inflamed eye and determine whether activation of two uveitogenic T cell subsets relies on different APCs and co-stimulatory molecules (Aim 1). In terms of determining the factors that are important for the activation and expansion of IL-17+ autoreactive T cells (Aims 2&3), our preliminary studies have shown that increased activation of IL-17+ T cells is frequently associated with activation of ?? TCR cells and that depletion of ?? T cells reduces induction of EAU. We will now determine whether depletion of ?? T cells prevent the Th17 uveitogenic T cells to acquire pathogenic activity and whether ?? -/- recipients will generate increased numbers of Th17-type uveitogenic T cells, if such mice are injected with a small number of ?? T subset (Aim2). We have observed that interaction between ??? and ?? T cell subsets results in the production of increased amount of IL-17. We will now determine the mechanisms that lead to reciprocal stimulation between ?? and ?? T cells and determine the role of ?? T cell subsets in immunoregulation on generation of IL17+ uveitogenic T cells. Our hypothesis is that """"""""exposure to infectious agents, such as microbial proteins, may promote ?? T cell activation. Activation of specific ?? subset(s) promotes the generation of IL17+ uveitogenic T cell;activated??? T cells may further promote the activation of ?? T cells, leading to augmented Th17 response."""""""" The continuation of this study and the clarification of the pathogenic role of, and relationship between, IFN-?+ 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 interested in the characterization of pathogenic T cells that cause this disease. We have developed a range of expertise in determining the cellular and molecular events crucial to the development of autoimmune disease. In this application, we propose to determine a new pathogenic T cell subset expressing interleukin-17 (IL-17).

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018827-02
Application #
7911703
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2009-09-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$403,425
Indirect Cost
Name
Doheny Eye Institute
Department
Type
DUNS #
020738787
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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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