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Priscilla Lee dissertation.pdf (9.37 MB)

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Defining pathways that promote and characterize pathogenic T cells in CNS autoimmunity

Lee, Priscilla
http://rave.ohiolink.edu/etdc/view?acc_num=osu1448984666

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which is though to be mediated by myelin-reactive CD4+ T cells. It reamins unclear that how these normally quiescent autoreactive T cells become encephalitogenic in MS patients. This study was designed to determine the signals that generate pathogenic T cells during differentiation and to identify the molecular pathways associated with the encephalitogenicity as a mechanism to identify potential therapeutic targets for multiple sclerosis. Using a myelin basic protein (MBP)-specific T cell receptor (TCR) transgenic mouse model, we observed that MBP-specific CD4+ T cells generated with antigen presenting cells (APCs) plus MBP antigen (Ag) were encephalitogenic; whereas T cells generated with anti-CD3/CD28 antibodies (Ab) were not, suggessting that APCs provided critical signals beyond TCR and co-stimulation molecule, contributing to the pathogenic phenotype. To recapitulate the signals provided by APCs, naive MBP-specific CD4+ T cells were activated with anti-CD3/CD28 Ab in the presence of various cytokines and were adoptively transferred into recipients to induce experimental autoimmune encephalomyelitis (EAE). The combination of IL-6/IL-23 or IL-12/IL-23 generated encephalitogenic T cells. IL-6 and IL-12 initiated the expression of IL-23R on naive T cells, and IL-23 further enhanced the expression of its own receptor and consequently the encephalitogenicity. Surprisingly, IL-23 activated STAT3, an established pathway under IL-23R, and STAT4, which was thought to be restricted to Th1 cells. There was a direct interaction between p-STAT3 and p-STAT4 upon IL-23 stimulation, suggesting that IL-23 signaled via p-STAT3/p-STAT4 heterodimers. Consistent with the pathogenic role of IL-23 observed in the mouse model, memory T cell from MS patients were hyper-reactive to IL-23, enhancing both p-STAT3 and p-STAT4. We found that not all myelin-reactive T cells were encephalitogenic. IL-6+TGF-ß-generated MBP-specific Th17 cells failed to transfer EAE; in contrast, MBP-specific Th17 cells differentaited with IL-6 plus neutralizing Ab to Th1/Th2 cytokines were encephalitogenic. Comparison of the non-encephalitogenic Th17 cells generated with two TGF-ß isoforms, TGF-ß1 or TGF-ß3, we found these cells expressed lower amounts of GM-CSF and IL-23R, both molecules necessary for encephalitogenicity. Thus TGF-ß, irrespective of isoforms, negatively regulated the differentiation of encephalitogenic Th17 cells. Similarly, MBP-specific Th1 cells differentiated with APC/Ag plus IL-12 induced severe EAE, but MBP-specific Th1 cells differentiated with anti-CD3/CD28 Ab plus IL-12 failed to efficiently transfer disease. To character the pathogenic phenotypes, we compared the gene expression profiles from encephalitogenic Th1/Th17 cells to non-encephalitogenic Th1/Th17 cells. Several molecules were shown uniquely expressed in mouse encephalitogenic Th1/Th17 cells and also highly expressed in memory T cells from MS patients. This provided potential targets that could be manipulated therapeutically as new treatments for MS. In summary, this work demonstrates several pathways that APCs influence on the encephalitogenicity of myelin-reactive T cells via cytokines. The findings also reveal the mechanisms by which naive autoreactive T cell become activated and thereby break peripheral tolarance. More broadly, these findings highlight the importance of the communication between immune cells and how this interaction shapes immune response in the context of normal settings or autoimmune diseases.
Amy Lovett-Racke (Advisor)
Virginia Sanders (Committee Member)
Natarajan Muthusamy (Committee Member)
Jonathan Godbout (Committee Member)
176 p.
Immunology

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Citations

  • Lee, P. (2015). Defining pathways that promote and characterize pathogenic T cells in CNS autoimmunity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1448984666

    APA Style (7th edition)

  • Lee, Priscilla. Defining pathways that promote and characterize pathogenic T cells in CNS autoimmunity. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1448984666.

    MLA Style (8th edition)

  • Lee, Priscilla. "Defining pathways that promote and characterize pathogenic T cells in CNS autoimmunity." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1448984666

    Chicago Manual of Style (17th edition)

osu1448984666
290
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This open access ETD is published by The Ohio State University and OhioLINK.