Thesis
Sublethal whole-body irradiation induces permanent loss and dysfunction in pathogen-specific circulating memory CD8 T cell populations
University of Iowa
Master of Science (MS), University of Iowa
Spring 2023
DOI: 10.25820/etd.007161
Abstract
The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation-exposure and associated immune dysfunction. However, the extent to which radiation-exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Formation of long-lasting memory lymphocytes is one of the foundational characteristics of adaptive immunity and the basis of many vaccination strategies. Following the rapid expansion and contraction of effector CD8 T cells, the surviving antigen (Ag)-specific cells give rise to the memory CD8 T cells that persist for a long time and are phenotypically and functionally distinct from their naïve counterparts. Significant heterogeneity exists within the memory CD8 T cell pool, as different subsets display distinct tissue localization preferences, cytotoxic ability, and proliferative capacity, but all memory CD8 T cells are equipped to mount an enhanced immune response upon Ag re-encounter. Using P14 CD8 T cells chimeric mice (P14 chimeras) with a LCMV infection model, we observed that sublethal (5Gy) whole body irradiation (WBI) induced a rapid decline in the number of naïve (TN) and P14 circulating memory CD8 T cells (TCIRCM) with the former being more susceptible to radiation-induced numeric loss. While TN cell numbers rapidly recovered, as previously described, the number of P14 TCIRCM cells remained low at least nine months after radiation-exposure. Additionally, the remaining P14 TCIRCM in irradiated hosts exhibited an inefficient transition to a central memory (CD62L+) phenotype compared to non-irradiated P14 chimeras. WBI also resulted in long-lasting T-cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag re-encounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with L. monocytogenes expressing the LCMV GP¬33-41 epitope relative to non-irradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation-exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in pre-existing TCIRCM, rendering previously-protected hosts susceptible to re-infection.
Details
- Title: Subtitle
- Sublethal whole-body irradiation induces permanent loss and dysfunction in pathogen-specific circulating memory CD8 T cell populations
- Creators
- Mohammad Heidarian
- 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 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007161
- Number of pages
- viii, 64 pages
- Copyright
- Copyright 2023 Mohammad Heidarian
- Language
- English
- Date submitted
- 04/21/2023
- Date approved
- 05/01/2023
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 56-64).
- Public Abstract (ETD)
Generation of memory CD8 T cells is the goal of many vaccination strategies and adaptive immune system to confer protection against intracellular infections and malignancies. Incidental or deliberate exposure of individuals to high levels of ionizing radiation is still a viable threat and a complicated public health issue. While the depleting effects of ionizing radiation on immune cells are established and clinically exploited for procedures that require rapid immune system suppression, the long-term impact of sublethal ionizing radiation on preexisting memory CD8 T cells remains unclear. Specifically, next to nothing is known about the quantity and quality of pre-existing memory CD8 T cells after the host is exposed to whole body irradiation. Here, we demonstrate that in addition to rapid loss of circulating memory CD8 T cells, ionizing radiation leads to a lasting lesion which prevents the surviving circulating memory CD8 T cells from numerically and functionally recovering. In short, surviving circulating memory CD8 T cells fail to re-establish the pre-radiation numbers, display long-lasting altered subset makeup, and show sub-optimal functionality. The long-lasting diminished number and function of circulating memory CD8 T cells lead to compromised protection of once-immunized irradiated hosts. These findings are a critical first step in development of treatments that aim to curb radiation-induced immunosuppression with high efficacy.
- Academic Unit
- Pathology
- Record Identifier
- 9984428940502771
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