Dissertation
Context matters: regulation and function of CD4 T cells responding to infection
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007342
Abstract
Malaria is a systemic disease caused by the Protozoan Plasmodium parasite with an estimated 249 million clinical cases and 608,000 deaths reported annually. Current therapeutic strategies fail to elicit sterilizing humoral immunity. Development of Plasmodium-specific humoral immunity is critically dependent on CD4 helper T cell responses and germinal center (GC) reactions during blood-stage Plasmodium infection. Thus, it remains important to refine our understanding of how the function of CD4 T cells distinctly regulates the development of Plasmodium-specific protective immunity. My thesis work focused on how CD4 T cell-derived cytokines regulate immune responses to murine Plasmodium infection. Using mouse models of blood-stage Plasmodium infection, I investigated whether sustained CD4 T cell-derived IL-21 in established germinal centers (GCs) is required for GC maintenance and output. Utilizing a novel inducible knockout mouse model that enabled timed deletion of Il21 in peripheral CD4 T cells, I found that memory B cells generated in the absence of IL-21 exhibited reduced recall function upon challenge. These data highlight that sustained IL-21 prevents premature cellular dissolution within the GC and promotes stringency of selective pressures during B cell fate determination required to produce high-quality Plasmodium-specific MBCs. These data additionally reveal that IL-21 regulates and supports selection of MBCs independent of type I and type II interferon signaling. These data are additionally consistent with a temporal requirement for IL-21 in fine-tuning humoral immune memory responses during experimental malaria. Together, my thesis work provides evidence that CD4 T cell functions program long-term protective immunity in a context dependent manner.
Details
- Title: Subtitle
- Context matters: regulation and function of CD4 T cells responding to infection
- Creators
- Jordan T. Johnson
- Contributors
- Noah S Butler (Advisor)Vladimir P Badovinac (Committee Member)Mary E Wilson (Committee Member)Priya D Issuree (Committee Member)Ryan A Zander (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007342
- Publisher
- University of Iowa
- Number of pages
- xiii, 99 pages
- Copyright
- Copyright 2024 Jordan T. Johnson
- Language
- English
- Date submitted
- 04/22/2024
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (page 90-99).
- Public Abstract (ETD)
Malaria is a devastating disease caused by Plasmodium parasites. An estimated 249 million clinical cases and 608,000 deaths are reported each year. Despite multiple preventative therapeutic and vaccination strategies, individuals fail to develop long-term protection.
CD4 T cells are an immune cell that provide essential help to other immune cells. In response to infection, CD4 T cells, a type of immune cell, can receive key signals to activate and promote specialized CD4 cell identities, including T follicular helper cells, Tfh. Tfh cells interact with B cells and secrete signaling proteins (cytokines) to generate protective antibody responses. Expanding our understanding of how CD4 T cells adopt these unique identities and provide optimal help in the immune response is important for improving therapeutic and vaccination strategies. My research has focused on whether the timing of when cytokines specifically act in response to Plasmodium infection impact the nature of help provided during the generation of protective immunity.
Using mouse models of experimental malaria, I found that a CD4 T cell secreted cytokine, IL-21, remains highly expressed after infection resolves to support B cells responses. Development of high-quality memory B cells that are capable of providing protection upon reinfection is impaired in the absence of sustained IL-21. I found IL-21 supports organization of B cells, selection of B cells to become memory B cells, and regulation of survival signals. These data provide evidence that the specific context of when CD4 T cells exert their function matters to drive protective immunity.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984647555502771
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