Date of Degree
PhD (Doctor of Philosophy)
Vladimir P. Badovinac
CD8 T cells play a critical role in the clearance of pathogenic bacteria, viruses, and protozoan parasites. Upon encountering their cognate antigen through either infection or vaccination, naïve CD8 T cells undergo robust proliferative expansion, which is followed by contraction and the formation of a memory population. Memory CD8 T cells are long-lived, and because they persist in increased numbers and possess enhanced functional abilities compared to naïve CD8 T cells, they are able to provide the host with increased protection following re-infection. Because of these properties, vaccines designed to elicit memory CD8 T cells have the potential to reduce health care burdens related to infection with pathogens including human immuno deficiency virus (HIV), malaria, influenza, and hepatitis virus. However, stimulating protective CD8 T cell responses against these pathogens through vaccination has proven challenging. Therefore, a better understanding of the properties of memory CD8 T cells generated following vaccination, and the characteristics of memory CD8 T cells best suited for providing protection against diverse pathogens is needed.
While memory CD8 T cells can be maintained for as long as the life of the host, evidence suggests that their properties change with time after infection. Because CD8 T cell-mediated protection is based upon both the numbers and quality or functional abilities of memory cells present at the time of re-infection, changes in memory CD8 T cell function over time could impact their ability to provide protection upon re-infection. Therefore, a better understanding of how memory CD8 T cells change with time after infection is needed. As part of the studies presented in this thesis, I found that the phenotype and function of memory CD8 T cells including localization, interleukin (IL)-2 cytokine production, responsiveness to homeostatic cytokines, metabolic capabilities, and proliferation and secondary memory generation potential change with time after infection. Interestingly functional changes could not be completely explained by changes in subset composition that occur with time, as changes over time were also seen in defined CD62Lhi subsets. Importantly, functional changes of memory CD8 T cells that occurred with time led to an increased ability to provide protection against a chronic viral infection. These data improve our knowledge of the capabilities of memory CD8 T cells generated following infection, and suggests that the outcome of vaccination strategies designed to elicit protective memory CD8 T cells using single or prime-boost immunizations will depend upon the timing between antigen encounters.
Following re-infection, memory CD8 T cells become activated and produce effector cytokines and cytolytic molecules that aid the host in clearing invading microbes. Activation can be triggered not only through cognate antigen recognition, but also by antigen-independent cytokine driven signals. However, our knowledge of how antigen-dependent and –independent signals contribute to CD8 T cell activation and protection following infection is incomplete. In the second part of my thesis, I show that the ability of memory CD8 T cells to become activated in response to inflammation decreases with time after infection, that antigen and inflammation act synergistically to induce activation of memory CD8 T cells, that the presence of cognate antigen enhances activation of memory CD8 T cells that contribute to clearance of infection, and that bystander memory CD8 T cell responses following unrelated bacterial infection do not provide the host with a protective benefit.
Together, the data in this thesis further our understanding of memory CD8 T cells generated following infection and/or vaccination, and the properties of memory CD8 T cells important for providing protection upon re-infection with invading pathogens.
Generating protective memory CD8 T cells through vaccination holds the potential for reducing public health threats from pathogens including HIV, malaria, influenza, and hepatitis virus. However, the pursuit of this goal has remained challenging, and a better understanding of the properties of memory CD8 T cells generated following infection and/or vaccination, and the characteristics of protective memory CD8 T cells is needed.
Memory CD8 T cells can be maintained for long-periods of time, but some of their functional properties have been shown to change with time after infection. I found that many functional abilities of memory CD8 T cells including effector cytokine production, metabolic capabilities, and proliferation following reinfection increase with time. Importantly, these changes led to increased memory CD8 T cell-mediated protection against chronic viral infection. Furthermore, I examined how antigen and inflammatory cytokine-induced activation of memory CD8 T cells is regulated, and the contributions of antigen-dependent and -independent memory CD8 T cell responses to protection following infection. I found that the ability of memory CD8 T cells to sense inflammation decreases with time after infection, that antigen promotes robust CD8 T cell responses following infection, and that bystander responses during non-related infection do not provide the host with a protective benefit. This data furthers our understanding of the properties of memory CD8 T cells generated following infection and/or vaccination and the characteristics of protective memory CD8 T cell responses. It suggests that the outcome of single and prime/boost vaccination will depend on the timing of re-infection.
publicabstract, Bacterial Infection, Memory CD8 T Cells, Protection from infection, Vaccination, Viral Infection
Copyright 2016 Matthew David Martin