The role of sepsis in shaping the naïve CD8 T cell compartment and factors that influence host’s susceptibility to sepsis
Creators: name: Berton, Roger-Ray
Publisher: name: University of Iowa
Year: 2023
Subjects: subject: CD8 T cell
subject: Sepsis
subject: public abstract
subject: Immunology
subject: FOS: Clinical medicine
subject: Inflammation

description: Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm that is followed by chronic immune dysfunction, termed immunoparalysis. While early intervention has improved the survival to the acute inflammatory event, those that survive the septic insult have a poor quality of life and require ongoing acute and long-term care. Consequently, the immunoparalysis phase of sepsis encompasses the majority of sepsis-associated deaths, because survivors have increased susceptibility to new and reencountering infections, viral reactivation, and increased cancer risk. Unfortunately, modest therapeutic progress for long-term sepsis-induced immunoparalysis has been made due to the lack of therapeutic translatability between mice and humans, in part, arising from extensive use of immune naïve mice in preclinical research. Thus, my thesis work focuses on the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool to elucidate mechanisms contributing to increased rates of disease following sepsis, and understanding factors that influence susceptibility to sepsis.
description: Utilizing a cecal ligation and puncture model of polymicrobial sepsis and longitudinal blood samples collected from healthy controls and septic patients, I demonstrate the naïve CD8 T cell pool undergoes profound long-term phenotypic and functional changes following a septic event. Polymicrobial sepsis induced Type I interferons early after the septic event, lead to increased representation of Ly6C expressing naïve CD8 T cells which generated more effector and memory cells, after subsequent viral challenge, than Ly6C- cells. However, naïve Ly6C+ CD8 T cells converted to central memory cells at a delayed rate. Further, naïve Ly6C+ CD8 T cells had increased bystander response than Ly6C-, but were immunoparalyzed compared to sham-derived cells following the septic event. This demonstrates a link between sepsis-induced inflammation and immunoparalysis in sepsis survivors, which may contribute to their associated risk to new and reencountering infections, and cancers.
description: Although I show sepsis-induced cytokine storm influences naïve CD8 T cells, I also demonstrate basal inflammation influences host’s susceptibility to sepsis. In particular, I developed a novel immunologically experienced murine model by sequential infections with well-studied human-relevant lab pathogens, to interrogate whether immunologic experience results in altered responses to subsequent challenges. Generation of immune experienced mice through controlled sequential infections enabled fine-tuning of the level of “experience” and inflammation prior to interrogating how this immunologic experience influences susceptibility to sepsis. Sequential infection of mice led to a transient increase in basal inflammation, and a long-term altered cellular composition and activation status of multiple leukocyte populations involved in pathogen control. By altering the time of sepsis induction, I show the level of basal inflammation controls sepsis-induced morbidity and mortality in immune experienced hosts. To establish if immune education alters cellular functions, prior to sepsis induction I depleted NK cells which increase survival to sepsis in immune naïve hosts. I found NK cells in immune experienced mice contribute to heightened basal inflammation, in turn, contributing to the increased mortality to sepsis, which contrasts their beneficial role in immune naïve hosts. Showing cellular functions can be impacted following immune education.
description: Cumulatively my thesis demonstrates how inflammation, both basal and sepsis-induced, influences outcomes following sepsis at host and cellular levels. Associating immune status and outcomes from sepsis highlighted the importance of understanding host comorbidities upon ICU admittance for sepsis. Additionally, my immune-educated model brings forth the significance of using murine models that mimic aspects of patients’ septic event in preclinical research, as new avenues for therapeutic approaches may need to be refined. Further, linking immune phases of sepsis, cytokine storm and immunoparalysis, reveals sepsis-induced inflammation contributes to the immunoparalysis phase by rearranging the naïve CD8 T cell compartment, which may reduce host capacity to respond to subsequent infections and cancers.