Display Full Text | Download Full Text
2.94 MB PDF file

Degree

Doctor of Philosophy, Case Western Reserve University, Pathology, 2010.

Abstract

Human autoimmune diseases such as psoriasis, multiple sclerosis, and rheumatoid arthritis are characterized by systemic T cell dysfunction, resulting in chronically activated Th1 and Th17 cells which are insufficiently suppressed by regulatory T cells. The data presented herein demonstrate that the pro-inflammatory cytokine IL-6 directly inhibits human regulatory T cell function, similar to its functions in the mouse. IL-6 is over-expressed in tissue and serum of patients with autoimmune diseases and is produced in high amounts by dermal dendritic cells and endothelial cells in the lesional skin of psoriasis patients. Upon T cell entry to the lesional skin, cells are exposed to high levels of IL-6, which likely contribute to their escape from regulation by Treg cells. We sought to determine the mechanism of action for the anti-tolerigenic properties of IL-6 by examining the signaling pathways downstream of IL-6R in primary human T cells. We show that in both effector and regulatory T cells, IL-6 preferentially signals through Stat3, with moderate activation of Stat1 and minimal MAPK/Erk activation. Inhibition of Stat3 signaling in mixed lymphocyte cultures containing IL-6 restores Treg-mediated suppression, demonstrating that IL-6-mediated loss of Treg suppression requires phosphorylation of Stat3. Criss-cross experiments, in which either effector or regulatory T cells were pre-treated with Stat3 inhibitors, show that pStat3 is required in both T cell populations for IL-6-mediated reversal of Treg function. Similarly, IL-21, which also signals preferentially through pStat3, induces a loss of Treg suppression, in contrast to signaling by IL-27 and IFN-gamma, which signal preferentially through Stat1 and do not inhibit suppression. Lastly, effector T cells stimulated strongly through the TCR are resistant to suppression by Treg and have concurrent Stat3 phosphorylation; inhibition of pStat3 restores functional suppression by Treg. Collectively, our data suggest that Stat3 signaling is crucial for mediating effector cell resistance to Treg suppression and that kinase-specific inhibitors may hold therapeutic promise for the treatment of autoimmune disease.

Subject Headings

Immunology

Keywords

T cell; Stat3; IL-6; psoriasis; autoimmunity

Committee / Advisors

Kevin Cooper, M.D. (Advisor)
Alan Levine, Ph.D. (Advisor)
Robert Fairchild, Ph.D. (Committee Chair)
Neil Greenspan, M.D./Ph.D. (Committee Member)
Eric Pearlman, Ph.D. (Committee Member)
Clive Hamlin, Ph.D. (Committee Member)

Pages

123p.

Document number: case1278433711
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=case1278433711

This ETD has been downloaded 155 times (through March 2013)