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

Klarquist, Jared
http://orcid.org/0000-0002-4072-3962
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023

Abstract Details

2016, PhD, University of Cincinnati, Medicine: 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.
Edith Janssen, Ph.D. (Committee Chair)
Divaker Choubey, Ph.D. (Committee Member)
Claire Chougnet, Ph.D. (Committee Member)
Michael Jordan, M.D. (Committee Member)
Jonathan Katz, Ph.D. (Committee Member)
295 p.
Immunology

Recommended Citations

Citations

  • Klarquist, J. (2016). Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023

    APA Style (7th edition)

  • Klarquist, Jared. Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023.

    MLA Style (8th edition)

  • Klarquist, Jared. "Type I IFN control of sterile inflammation: Uncovering mechanisms behind autoimmunity and antitumor immunity." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1467988023

    Chicago Manual of Style (17th edition)

ucin1467988023
603
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This open access ETD is published by University of Cincinnati and OhioLINK.