Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity

Bibliographic Details
Main Author:	Klarquist, Jared
Language:	English
Published:	University of Cincinnati / OhioLINK 2016
Subjects:	Immunology
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14679880232021-08-03T06:37:20Z Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity Klarquist, Jared Immunology Dying cells elicit immune responses toward self antigens which can be either harmful or beneficial. These responses can help control deadly cancers, or they can destroy healthy tissues and initiate debilitating autoimmune diseases. We have sought to define novel mechanisms that drive sterile inflammatory responses toward self antigens which may be exploited in new cancer immunotherapies or in treatments for autoimmune diseases. Type I interferon (IFN) has been described as a central mediator in bridging innate and adaptive immune responses toward cell-associated antigens, but the pathways both up- and downstream of IFN signaling have remained unclear. Our studies demonstrate that the stimulator of IFN genes (STING) induces type I IFN production by dendritic cells (DCs) in response to dying cell-derived cytosolic DNA. Further, we report that the IFN produced by DCs results in a positive feedback loop, enhancing their ability to prime effective and long-lasting CD8 T cell responses toward tumor cell-associated antigens. Moreover, we found that STING is also critical to driving autoimmune responses in the bm12 chronic graft-versus-host disease model of systemic lupus erythematosus (SLE). Within the context of bm12 autoimmunity, we determined that type I IFN sensing by CD4 helper T cells protected them from being killed by highly active natural killer (NK) cells, thereby augmenting autoimmune disease. We also showed that direct sensing of IFN enhanced the development of germinal center B cells and plasmablasts in an NK-independent manner. Lastly, we defined the metabolic programs of key T cell and B cell subsets, uncovering a fundamental role for glycolysis in these autoimmune responses. Together, our studies shine light on previously undescribed pathways controlling anticancer immune responses and autoimmunity, providing opportunities for the development of nuanced treatment strategies which may prove both more specific and more effective than existing therapies. 2016-09-30 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023 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
spellingShingle	Immunology Klarquist, Jared Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity
author	Klarquist, Jared
author_facet	Klarquist, Jared
author_sort	Klarquist, Jared
title	Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity
title_short	Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity
title_full	Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity
title_fullStr	Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity
title_full_unstemmed	Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity
title_sort	type i ifn control of sterile inflammation: uncovering mechanisms behind autoimmunity and antitumor immunity
publisher	University of Cincinnati / OhioLINK
publishDate	2016
url	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023
work_keys_str_mv	AT klarquistjared typeiifncontrolofsterileinflammationuncoveringmechanismsbehindautoimmunityandantitumorimmunity
_version_	1719440525664190464

Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity

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