Degree
Doctor of Philosophy (PhD)
Department
Pathobiological Sciences
Document Type
Dissertation
Abstract
Influenza (flu) virus infections are a leading cause of respiratory illness. Globally there are approximately 290,000-650,000 deaths and 3-5 million cases of severe illness during the average flu season. Severe flu infection is associated with the combination of a strong pro-inflammatory and weak anti-inflammatory response. Regulatory T cell subsets suppress pro-inflammatory responses during flu infection, with production of the immunomodulatory cytokine IL-10 playing a critical role in this process. Tissue resident regulatory T cell subsets are maintained within nonlymphoid tissues and are optimally positioned to suppress localized pro-inflammatory responses. However, knowledge of the signaling pathways regulating the development of tissue resident regulatory T cell populations during flu infection is limited. We utilized mouse adapted strains of flu and a Foxp3RFP/IL-10GFP dual reporter mouse model to define the signaling pathways regulating the development of two tissue resident regulatory T cell populations, Foxp3+CD4+ regulatory T (Treg) cells and IL-10-producing CD8+ T cells.
We characterized the tissue resident Foxp3+Treg cell response during heterosubtypic influenza infections and found that blockade of signaling through the immune checkpoint molecules ICOS and PD-1 counter-regulated expansion and IL-10 production. Furthermore, mice deficient in IL-2 inducible T cell kinase (ITK), a critical signaling mediator downstream of the T cell receptor (TCR), displayed reduced development of IL-10-producing CD8+ T cells coinciding with increased mortality and cellular recruitment in the lungs during acute flu infection. PD-1 signaling blockade and exogenous IL-2 rescued the development of IL-10-producing CD8+ T cells in Itk-/- mice. Utilizing a coculture system and adoptive transfer model, we found cell intrinsic and extrinsic ITK were required for optimal IL-10-producing CD8+ T cell development. Furthermore, IL-10 production by CD8+ T cells was regulated by the ITK/PI3K/AKT/mTOR/HIF-1a pathway. Finally, we found inhibition of ITK kinase activity in fully developed IL-10-producing CD8+ T cells resulted in increased ability to suppress naïve T cell expansion.
In conclusion, this work characterizes two distinct tissue resident regulatory T cell populations and signaling pathways regulating their development during flu infection. Our work suggests that targeting TCR and immune checkpoint signaling pathways may be a viable option to modulate the development of tissue resident regulatory T cells and immunopathology during flu infection.
Date
7-11-2023
Recommended Citation
McGee, Michael, "Tissue Resident Regulatory T Cells and Immunopathology During Influenza Infections" (2023). LSU Doctoral Dissertations. 6236.
https://repository.lsu.edu/gradschool_dissertations/6236
Committee Chair
Weishan Huang