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T CELL RECEPTOR SIGNAL STRENGTH AND ANTIGEN AFFINITY DIFFERENTIALLY REGULATE CD8+ MEMORY T CELL DEVELOPMENT

Author
Solouki, Sabrina
Abstract
CD8+ T cells play a critical role in adaptive immunity by maintaining the ability to differentiate into CD8+ memory T cells, which provide the basis of protective immunity. During an intracellular infection, CD8+ T cells pass through several characteristic phases before becoming mature memory cells. Initial antigen stimulation causes naïve CD8+ T cells to clonally expand and differentiate into short-lived effector cells (SLECs). Subsequently, SLECs undergo a contraction phase, whereby the majority of surviving cells are known as memory precursor effector cells (MPECs); 5-10% of the MPECs survive the initial contraction phase from SLECs to further develop into CD8+ memory T cells. In my dissertation, we show that two distinct parameters: T cell Receptor (TcR) signal strength (regulated by the tyrosine kinase Itk) and antigen affinity, play important but separate roles in modulating the development of memory CD8+ T cells. We found that reducing both TcR signal strength and antigen affinity for the TcR leads to enhanced and accelerated development of CD8+ memory T cells. Additionally, TcR signal strength is able to regulate CD8+ T cell effector cytokine production independent of TcR antigen affinity. Analysis of RNA-sequencing data reveals that genes for inflammatory cytokines/cytokine receptors are significantly altered upon changes in antigen affinity and TcR signal strength. Furthermore, our findings show that the inflammatory milieu is critical in regulating this TcR signal strength mediated increase in memory development as both CpG treatment or co-transfer of WT and Itk-/- T cells eliminates the observed increase in memory cell formation. These findings suggest that TcR signal strength and antigen affinity independently contribute to CD8+ memory T cell development, which is modulated by inflammation, and suggest that manipulating TcR signal strength, along with antigen affinity, may be used to tune the development of CD8+ memory T cells during vaccine development.
Description
169 pages
Date Issued
2020-05Committee Chair
August, Avery
Committee Member
Rudd, Brian; Grimson, Andrew
Degree Discipline
Biomedical and Biological Sciences
Degree Name
Ph. D., Biomedical and Biological Sciences
Degree Level
Doctor of Philosophy
Rights
Attribution-NoDerivatives 4.0 International
Type
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NoDerivatives 4.0 International