Dissertation
NK cell responses control and define the sepsis-induced cytokine storm and immunoparalysis state
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2020
DOI: 10.17077/etd.005707
Abstract
Sepsis is a dysregulated host response to systemic infection that leads to immunologic dysfunction and organ damage. This dysregulated host response, termed the cytokine storm, is composed of both pro- and anti-inflammatory cytokines that are detrimental or beneficial to host survival, respectively. While early intervention has improved survival of the acute inflammatory event, approximately 20% of people still succumb to the cytokine storm. Frustratingly, >100 phase II and II clinical trials aimed at limiting pro-inflammatory cytokines have failed indicating a greater need to understand the cytokine storm in order to improve patient outcomes. Yet, even as survival of the septic event has increased, it has become apparent that septic patients experience a prolonged state of immunologic dysfunction, termed immunoparalysis, that reduces host capacity to respond to secondary infections. My thesis work focuses on Natural Killer (NK) cells to understand the interplay between cellular responses and the septic event, this is with respect to both how NK cells influence septic inflammation and how NK cells become impaired contributing to the immunoparalysis state.Utilizing a cecal ligation and puncture model of sepsis, I demonstrate that NK cells are beneficial to host survival during sepsis by limiting the duration of the cytokine storm. Further, NK cells produced IL-10 in response to IL-15 released during the septic insult. This demonstrates a linkage between the pro-inflammatory (IL-15) and anti-inflammatory (IL-10) phases of septic inflammation. Critically, this NK cell-derived IL-10 supported host survival during sepsis demonstrating that NK cells control the severity of the septic event. NK cell-derived IL-10 was also relevant to septic patients and corresponded to the severity of the septic event.
Yet, even as NK cells influence the cytokine storm, sepsis also impacts NK cells. I further demonstrated that sepsis leads to a profound apoptotic loss of NK cells and that those NK cells that survive have a distinct transcriptional profile. Changes in this transcriptional profile included intrinsic deficits in NK cell capacity to undergo both cytokine- and activating receptor-mediated effector function. Response to cytokine was impaired by reduced receptor expression thereby reducing NK cell effector cytokine (interferon [IFN]) production during Listeria monocytogenes (L.m.) infection. Additionally, while NK cell expression of the activating receptor Ly49H was not influenced by sepsis; the capacity of Ly49H, and related receptors, to signal was substantially impaired. This was due to a loss in the expression of DNAX activation protein of 12kDa (DAP12) a critical adaptor protein for Ly49H. Due to the numerical and intrinsic functional impairments in Ly49H NK cells, host capacity to control murine cytomegalovirus (MCMV) infection, for which Ly49H NK cells are critical effectors, was reduced. However, administration of lymphoproliferative interleukin-2 complexes (IL-2c) was able to increase the number of Ly49H NK cells and host capacity to control MCMV infection despite a lack of improvement in the intrinsic function of Ly49H. These results demonstrate how NK cells define the sepsis-induced immunoparalysis state.
Cumulatively my thesis demonstrates how NK cells influence and are influenced by the cytokine storm. By linking the pro- and anti-inflammatory phases of the septic inflammation NK cells serve as critical mediators of disease severity through their capacity to participate in both inflammatory responses. Further, their dysfunction as a result of the cytokine storm highlights how sepsis leads to numerical and intrinsic functional impairment of lymphocytes. These impairments in turn reduce host capacity to respond to secondary infections thereby defining the immunoparalysis state through their dysfunction.
Details
- Title: Subtitle
- NK cell responses control and define the sepsis-induced cytokine storm and immunoparalysis state
- Creators
- Isaac James Jensen
- Contributors
- Vladimir P Badovinac (Advisor)Hai-Hui Xue (Committee Member)John T Harty (Committee Member)Jon C Houtman (Committee Member)Kevin L Legge (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Autumn 2020
- DOI
- 10.17077/etd.005707
- Publisher
- University of Iowa
- Number of pages
- xvi, 179 pages
- Copyright
- Copyright 2020 Isaac James Jensen
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (page 158-179).
- Public Abstract (ETD)
When an infection is poorly managed and enters the bloodstream, this evokes a vigorous but improper immune response. This improper response involves both pro- and anti-inflammatory mediators, called the cytokine storm, that can lead to organ damage and death. Identification and treatment of the symptoms of the cytokine storm has advanced, yet we are unable to limit the severity of the inflammation. This is because the good (anti-inflammatory) and bad (pro-inflammatory) parts of the cytokine storm are linked. Thus, I first identified how these pro- and anti-inflammatory phases of sepsis are linked through natural killer (NK) cells. NK cells can contribute to both aspects of the cytokine storm but are overall beneficial since they produce an anti-inflammatory cytokine [IL-10] in response to a pro-inflammatory cytokine [IL-15]. This work links the phases of the septic inflammation and will improve therapeutic strategies to limit the cytokine storm. However, even after the inflammation resolves, individuals can have long-term immune problems that prevent them from fighting infections. So, I next addressed how NK cells, that are important for controlling infections, lose their ability to fight infection. Sepsis reduced the number of NK cells and those NK cells that were present were less able to recognize inflammation or diseased cells, ultimately preventing them from fighting infections. Fortunately, if the number of NK cells is bolstered hosts could better fight off infection, despite the diminished function of the NK cells. This dissertation will provide insight into therapies to improve host ability to fight infection after sepsis.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9984035795702771
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