Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Haeryfar, Mansour

Abstract

Sepsis causes millions of deaths every year with 70% of them being attributed to the immunosuppressive phase of the syndrome, which occurs shortly after the onset and leads to a severe immunodeficiency. Currently, there is not enough known about antigen specific CD8+ T cell responses during the immunosuppressive phase of sepsis and the studies that have been done, have shown controversial findings. In my thesis research, I have utilized the cecal ligation and puncture (CLP) model of polymicrobial sepsis – which closely mimics the progression of human sepsis – to study antigen specific CD8+ T cell responses by examining their exhaustion phenotype and functionality. Contrary to my initial thoughts, I had discovered that primary and recall CD8+ T cell responses are enhanced during protracted sepsis within the spleen. I demonstrated that antigen specific CD8+ T cells were higher in frequency within the septic spleen; however, they possessed similar absolute numbers compared to the sham control. Additionally, these antigen specific CD8+ T cells had an increased functionality as demonstrated by their increased ability to produce IFN-gamma and granzyme B, while maintaining their polyfunctionality. Furthermore, I also discovered that antigen specific CD8+ T cells within the septic spleen were phenotypically more exhausted as these cells had an enhanced co-expression of the different exhaustion markers examined. Herein, I conclude that sepsis-induced immunosuppression leads to an enhanced antigen specific CD8+ T cell response within the spleen, which is an important finding as it currently contrasts the commonly thought notion that CD8+ T cell responses are dampened during protracted sepsis. This research may alter the way we think about sepsis-induced immunosuppression as I have shown that antigen specific CD8+ T cell responses were enhanced, rather than dampened.

Summary for Lay Audience

Sepsis is a severe syndrome, which causes millions of deaths every year and is currently one of the leading causes of death in the intensive care unit (ICU). Sepsis is characterized as a syndrome that has two distinct phases. The onset of sepsis is characterized by a hyper- inflammatory state, which is relatively short-lived and causes significant mortality; however, the subsequent immunosuppressive phase causes the majority of deaths from this deadly syndrome in developed countries with better critical care facilities. During the second phase of the syndrome, patients are often quite susceptible to infections caused by either newly encountered or previously encountered microbial species. My thesis research has focused on a specific immune cell subset named CD8+ T cells, which are critical for responding to a variety of disease-causing organisms, including new and old microbes. CD8+ T cells are highly specific for microbes that are encountered, and they develop into memory CD8+ T cells, which deal with an infection that has been previously encountered. During sepsis, these cells are reportedly impaired in their ability to deal with microbes. I set out to better understand these cells during sepsis-induced immunosuppression by looking at their frequencies, absolute numbers, cell surface expression of different molecules, which would give us insight into their activation state and function. In my research, I used a clinically relevant mouse model of sepsis-induced immunosuppression and examined specific antiviral CD8+ T cell responses. Contrary to what has been thought previously, I found that memory CD8+ T cells specific for Influenza A Virus (IAV), to my surprise, were higher in frequency, showed signs of increased activation and exhaustion, and were more functionally active during a memory response within the spleen. This was also recapitulated when I investigated primary CD8+ T cell responses to newly encountered IAVs. Currently, it is viewed that CD8+ T cell responses are less activated and less functional within the immunosuppressive phase of sepsis; however, herein I show that they are more activated and functional, which contradicts the current notion.

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