IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells

IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells

Bibliographic Details
Main Author: Goodman, Wendy Ann
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2010
Subjects:
Immunology
T cell
Stat3
IL-6
psoriasis
autoimmunity
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1278433711
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case12784337112021-08-03T05:33:51Z IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells Goodman, Wendy Ann Immunology T cell Stat3 IL-6 psoriasis autoimmunity 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. 2010 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1278433711 http://rave.ohiolink.edu/etdc/view?acc_num=case1278433711 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Immunology
T cell
Stat3
IL-6
psoriasis
autoimmunity
spellingShingle Immunology
T cell
Stat3
IL-6
psoriasis
autoimmunity
Goodman, Wendy Ann
IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells
author Goodman, Wendy Ann
author_facet Goodman, Wendy Ann
author_sort Goodman, Wendy Ann
title IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells
title_short IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells
title_full IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells
title_fullStr IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells
title_full_unstemmed IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T Cells
title_sort il-6 signals through pstat3 to prevent functional immune suppression by human regulatory t cells
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2010
url http://rave.ohiolink.edu/etdc/view?acc_num=case1278433711
work_keys_str_mv AT goodmanwendyann il6signalsthroughpstat3topreventfunctionalimmunesuppressionbyhumanregulatorytcells
_version_ 1719421760177176576

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