Date of Degree
PhD (Doctor of Philosophy)
Vladimir P. Badovinac
Memory CD8 T cells offer increased protection to immune hosts by rapidly eliminating pathogen-infected cells during re-infection. Generating and sustaining a protective memory CD8 T cell response is considered a hallmark of adaptive immunity. Extensive research has been devoted to understanding the parameters affecting memory CD8 T cell generation after infection or immunization in order to design the most effective vaccines. An accepted notion in the field is that increased protection from re-infection is afforded by the generation of a large number of memory CD8 T cells. Consecutive prime-boost immunization strategies that elicit secondary responses are often used to increase the absolute numbers of memory CD8 T cells. While parameters affecting the generation of primary memory CD8 T cells are well known, the factors influencing the development of re-stimulated secondary CD8 T cell responses remain understudied.
Here, I addressed the mechanisms involved in the generation and development of secondary memory CD8 T cells. I found that the time at which primary memory CD8 T cells enter into an immune response during re-infection impacts their fate and differentiation into secondary memory CD8 T cells. Late-entry of primary memory CD8 T cells into an immune response (relative to the initiation of infection) not only facilitates expression of transcription factors associated with memory formation in secondary effector CD8 T cells, but also influences the ability of secondary memory CD8 T cells to localize within the lymph nodes, produce interleukin-2 cytokine (IL-2), and undergo robust antigen-driven proliferation. The timing of stimulation of primary memory CD8 T cells also impacts the duration of expression of the high-affinity IL-2 receptor (CD25) on secondary effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing secondary CD8 T cells, I verify the role of IL-2 in controlling the differentiation of secondary CD8 T cell responses. The data I present herein suggest that the process of primary memory-to-secondary memory CD8 T cell differentiation is not fixed and can be manipulated, a notion with implications in the design of future prime-boost vaccination approaches.
Although vaccines are designed and intended to benefit a range of individuals, at times the efficacy of a vaccination regime depends on the overall health status of a host. Thus, in another portion of my thesis work I explored the extent to which obesity compromises the differentiation and maintenance of protective memory CD8 T cell responses. I found that diet-induced obesity did not impact the maintenance of pre-existing memory CD8 T cells, including their acquisition of a long-term memory phenotype (i.e., CD27hi, CD62Lhi, KLRG1low) and function (i.e., cytokine production, antigen-driven secondary expansion, and memory CD8 T cell-mediated protection). Additionally, diet-induced obesity did not influence the differentiation and maintenance of newly evoked memory CD8 T cell responses, in inbred and outbred hosts, that were generated in response to different types of systemic (LCMV, L. monocytogenes) and/or localized (influenza virus) infections. Interestingly, I found that the rate of naïve-to-memory CD8 T cell differentiation after a peptide-coated dendritic cell immunization was similar in lean and obese hosts. This suggests that obesity-associated inflammation is unlike pathogen- or adjuvant-induced inflammation, and does not influence the development of an endogenous memory CD8 T cell response. My studies reveal that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either primed before or after obesity is established. This is a surprising notion with implications for future studies aiming to elucidate the role of obesity in susceptibility to infection and vaccine efficacy.
Collectively, the data presented here further the understanding of memory CD8 T cell responses in contexts of health and disease.
Memory CD8 T cell-mediated immune responses are essential for protective immunity, as these cells are endowed with functional abilities that allow elimination of infected cells. To design the most effective vaccine strategy intended to elicit a robust memory CD8 T cell response, thorough evaluation of parameters influencing their generation and maintenance is required.
Consecutive prime-boost vaccination strategies that elicit secondary immune responses are often implemented to increase overall numbers of memory CD8 T cells. However, factors influencing the development of re-stimulated secondary CD8 T cells remain unknown. I demonstrate in my thesis that the time at which primary memory CD8 T cells encounter antigen and are re-stimulated during an infection influences the outcome of a secondary CD8 T cell response. Additionally, interleukin-2 cytokine signals received by developing secondary CD8 T cell impacts the rate of acquiring secondary memory CD8 T cell characteristics. These data indicate that secondary memory CD8 T cell generation is a process that can be manipulated, which has relevance for the design of consecutive prime-boost immunization strategies.
Another part of my work focuses on how the growing epidemic of obesity impacts the generation and maintenance of a protective memory CD8 T cell response. I show that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either evoked before or after obesity is established. This is a surprising finding with implications for future studies aiming to understand the role of obesity in susceptibility to infection and vaccine efficacy.
publicabstract, Diet-Induced Obesity, Inflammation, Memory CD8 T Cells, Pathogen, Prime-Boost, Secondary Memory
Copyright 2015 Shaniya H Khan