Thesis
Impact of sepsis on pathogen-specific circulating and resident memory CD8 T cell subsets
University of Iowa
Master of Science (MS), University of Iowa
Autumn 2021
DOI: 10.17077/etd.006314
Abstract
The immunoparalysis phase of sepsis is characterized by deficits in the adaptive immune response, leading to patients succumbing to infections that would otherwise be controlled by a healthy immune system. Understanding how sepsis alters different memory CD8 T cell subsets is crucial for the design of future treatments aimed at increasing T cell immunity in sepsis survivors. We thus sought to understand how the severity of the septic event impacts circulating and resident memory CD8 T cell populations by inducing moderate (0-10% mortality) or severe (~50% mortality) sepsis via cecal ligation and puncture (CLP). When compared to moderate sepsis, severe sepsis led to increased morbidity and mortality as well as increased systemic inflammation. Severe sepsis also led to increased vascular permeability as measured by Evans Blue. Compared to circulatory memory CD8 T cells, moderate sepsis does not result in the numerical decline of tissue resident memory CD8 T cells (Trm) which retain their “sensing and alarm” IFNɣ-mediated effector function. Interestingly, after severe sepsis, skin CD103+ CD8 Trm underwent apoptosis and subsequent numerical loss following severe sepsis, which was not observed in mice that experienced moderate CLP or sham surgeries. Consequently, severe septic mice showed diminished CD8 T cell-mediated protection to localized skin re-infection. Finally, the relationship between severity of sepsis and demise in circulatory vs tissue-embedded CD8 T cell populations was confirmed by examining tumor-infiltrating and non-specific CD8 T cells in B16 melanoma tumors. Thus, sepsis can differentially affect the presence and function of Ag-specific CD8 T cells that reside inside tissues/tumors depending on the severity of the insult, a notion with direct relevance to sepsis survivors and their ability to mount protective memory CD8 T cell dependent responses to localized re-encounter. The numerical loss and functional impairment of memory CD8 T cells have been previously documented after sepsis. However, these studies focused on the primary memory CD8 T cell response, leaving the influence of sepsis on the function, phenotype, and localization of higher-order memory CD8 T cells unknown. Using a sequential co-adoptive transfer model, we demonstrate that primary (1M) and quaternary memory CD8 T cells (4M) are equally susceptible to sepsis-induced numerical loss. We observed an increase in the proliferation of both 1M and 4M CD8 T cells in response to the sepsis-induced lymphopenic environment in CLP hosts, with 1M CD8 T cells proliferating to a greater degree than 4M CD8 T cells. The sepsis-induced proliferation resulted in an increased representation of 1M CD8 T cells compared to 4M CD8 T cells, suggesting 1M CD8 T cells retain biological mechanisms to outcompete 4M CD8 T cells in the circulation. In comparison to 1M CD8 T cells in Sham controls, 1M CD8 T cells in CLP hosts had increased IL-15 receptor expression, allowing for an increased ability to receive pro-survival signals. Finally, we observed a significant increase in the frequency of 1M CD8 T cells producing IL-2, supporting existing literature showing the accelerated conversion to a T central memory (Tcm) phenotype following sepsis. In total, these findings help better our understanding of the chronic immunoparalysis phase of sepsis and may inform future immunotherapies designed to improve immunity of sepsis survivors.
Details
- Title: Subtitle
- Impact of sepsis on pathogen-specific circulating and resident memory CD8 T cell subsets
- Creators
- Steven James Moioffer
- Contributors
- Vladimir P Badovinac (Advisor)John T Harty (Committee Member)Kevin L Legge (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Pathology
- Date degree season
- Autumn 2021
- Publisher
- University of Iowa
- DOI
- 10.17077/etd.006314
- Number of pages
- xiii, 111 pages
- Copyright
- Copyright 2021 Steven James Moioffer
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 98-111).
- Public Abstract (ETD)
Sepsis is a life-threatening condition that occurs after a hyperactive immune response to an infecting pathogen that has spread throughout the body. The majority of septic patient deaths are due to unrelated infections that cannot be controlled because of an impaired immune system, a phase known as immunoparalysis. We addressed how sepsis influences different types of memory CD8 T cells, a keystone immune cell that “remembers” previously encountered pathogens.
We first asked how the severity of the initial septic event impacts memory CD8 T cells in the blood (T circulating memory - TCIRCM) and in the skin (T resident memory – Trm). We found that severe sepsis resulted in increased death and inflammation in comparison to moderate sepsis. We also saw increased “leakiness” of blood vessels and increased inflammation within peripheral tissues. Severe sepsis caused the programmed death of CD8 Trm cells, which decreased their abundance in the skin, something that does not occur in moderate sepsis. The loss of these Trm cells resulted in the mouse being more vulnerable to the same infection. Finally, we observed a decrease in the number of memory CD8 T cells within tumors after severe sepsis, suggesting that the severe sepsis causes the loss of CD8 T cells that reside within tissues. These findings are important in understanding how the severity of the septic event influences the chronic immunoparalysis phase.
Since most sepsis research focuses on memory CD8 T cells that have seen the pathogen they “remember” once (primary memory – 1M), we next asked how moderate sepsis impacts memory CD8 T cells that have encountered the pathogen they “remember” four separate times (quaternary memory – 4M). We observed the equal loss of 1M and 4M CD8 T cells after sepsis. However, 1M CD8 T cells divided more after sepsis, leading to an increased representation in the blood compared to 4M CD8 T cells. This increase was supported by an improved ability of 1M CD8 T cells to sense survival signals, allowing them to outcompete 4M CD8 T cells. Finally, we saw that sepsis accelerated the conversion of 1M CD8 T cells to a specific subpopulation, all of which are important considerations when thinking of how sepsis survivors may fare against future infections.
- Academic Unit
- Pathology
- Record Identifier
- 9984210749002771
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