Thesis
The ability of memory CD8 T cell subsets to numerically and functionally recover following whole body irradiation is influenced by their history of cognate antigen exposures
University of Iowa
Master of Science (MS), University of Iowa
Spring 2025
DOI: 10.25820/etd.007936
Abstract
The increasing use of radiation in energy and research sectors, medical practices, and an increasing sector dedicated to expanding space travel mean that the average risk of radiation exposure has increased within the past decade. Importantly, radiation exposure has been shown to cause immune cell death, leading to lymphopenia, and long-term immune impairment of survivors. While the effect of radiation on CD8 T cells has been explored, further research is necessary to elucidate the effect across heterogeneous CD8 T cell subsets. One of the hallmarks of protective immunity is the development of memory CD8 T cells. Naïve CD8 T cells specific to a given antigen (Ag) are exposed to said antigen through either infection or vaccination, prompting proliferation and the generation of an effector CD8 T cell pool, before production of memory CD8 T cells that are maintained for the life of the host. These memory CD8 T cells are then able to respond to a repeat cognate-Ag challenge much faster than their naïve counterparts, and they provide strong protection against intracellular pathogens and tumor cells. With each additional cognate-Ag exposure (be it from recurrent infection, re-emergence of latent infections, or additional vaccine doses), the resultant memory CD8 T cell pools further differ from naïve CD8 T cells in their kinetics upon rechallenge, tissue distribution, gene expression, function, and phenotype. How radiation effects these repeatedly-stimulated memory CD8 T cells is not known. Using P14 Tcr-Tg Thy disparate CD8 T cells and a series of adoptive transfers, we created C57Bl6 (B6) mice containing two allelically distinct populations of memory CD8 T cells: primary memory (1M) CD8 T cells and quaternary memory (4M) CD8 T cells. Mice were administered either 0Gy (mock) or 5Gy whole body irradiation (WBI). 1M CD8 T cells and 4M CD8 T cells proved equally susceptible to radiation-induced cell death. Surviving memory CD8 T cells had intrinsic defects in cytokine production upon ex vivo peptide stimulation and in proliferation upon in vivo viral challenge. While both cell populations showed signs of attempted cell cycling early after WBI, neither population numerically recovered to pre-WBI levels, and indeed, 4M CD8 T cells were eventually lost from the PBL. Finally, long-term phenotypic differences were noted, where both 1M CD8 T cells and 4M CD8 T cells displayed a delay in their natural transition to a central memory (Tcm) dominant phenotype. This, in turn, lead to changes in the composition of the memory CD8 T cell compartment in which the representation of memory CD8 T cells with history of repeated Ag stimulations was further reduced. Thus, numerical and functional recovery of memory CD8 T cells generated after repeated infections/vaccinations in radiation survivors is severely impaired. This raises concerns for the efficacy of protection previously generated against recurring infections and the ability for the immune system to effectively respond to future vaccinations.
Details
- Title: Subtitle
- The ability of memory CD8 T cell subsets to numerically and functionally recover following whole body irradiation is influenced by their history of cognate antigen exposures
- Creators
- Elizabeth Escue
- 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
- Spring 2025
- DOI
- 10.25820/etd.007936
- Publisher
- University of Iowa
- Number of pages
- x, 94 pages
- Copyright
- Copyright 2025 Elizabeth Escue
- Language
- English
- Date submitted
- 04/15/2025
- Description illustrations
- Illustrations, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 84-94).
- Public Abstract (ETD)
Memory CD8 T cells are critical for protection against intracellular pathogens and malignancies. Vaccine booster strategies specifically aim to generate so-called “higher order” memory CD8 T cell populations, which have different properties than primary memory (1M) CD8 T cell populations, by repeatedly exposing existing memory CD8 T cells to their cognate antigen. Thus, these cells can also arise from recurrent infections. It has been shown that irradiation severely damages the naïve and 1M CD8 T cell compartments, but not much is known about its effect on higher order memory CD8 T cell populations. To create effective therapies for radiation survivors, we need to understand how radiation affects all components of the total CD8 T cell memory. Here, we demonstrate that radiation differentially influences CD8 T cells with single or multiple antigen encounters. These cell types were equally susceptible to radiation induced cell death and both acquired functional deficits. Compared to 1M CD8 T cells, irradiated higher order memory CD8 T cells expanded the least in response to new infection and were the only population that displayed a continuous numerical loss. This, in turn, leads to changes in the composition of the memory CD8 T cell compartment in which the representation of higher order memory CD8 T cells is further reduced. Thus, radiation survivors remain immunocompromised and are likely vulnerable to infections they were previously immunized against. These long-term defects in memory CD8 T cell populations need to be considered when assessing the efficacy of therapeutics and future vaccinations in patients with previous radiation exposure.
- Academic Unit
- Pathology
- Record Identifier
- 9984831230902771
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