Advisory Committee Chair
Laurie E Harrington
Advisory Committee Members
Charles O Elson
Robinna G Lorenz
Craig L Maynard
Lesley Smythies
Claude Steele
Document Type
Dissertation
Date of Award
2019
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
The Innate Lymphoid Cell (ILC) population encompasses five subpopulations that are increasingly appreciated to participate in immune responses to inflammation and injury as well as directly influence homeostasis in tissues throughout the body. ILCs are enriched at mucosal surfaces, such as the gastrointestinal tract, where they are transcriptionally poised for rapid activation. Therefore, ILCs contribute significantly to protective responses to infection, and can exacerbate inflammation and disease when dysregulated. Herein, we demonstrate two pathways that regulate intestinal ILC phenotype and function and delineate the impact of these pathways on both protective and pathogenic roles of ILCs. Using a murine model of gastrointestinal Listeriosis, we find ILCs to be essential for control of intestinal bacterial burden and prevention of systemic dissemination. Specifi-cally, we observed proliferative and cytokine responses by Group 1 and 3 ILCs (ILC1s and ILC3s, respectively) following infection with L. monocytogenes. Innate STAT4 signaling was required for protection and to mount a protective IFNγ response. In contrast to Th1 cells, STAT4 is dispensable for the development of intestinal ILC populations, but it is re-quired for IFNγ production by ILC1s and a subpopulation of ILC3s. Altogether, these data identify the STAT4-IFNγ axis as essential for ILC-mediated protection against gastrointes-tinal infection. We also find a role for IL-21 in directing the phenotype and function of intestinal ILC3s. IL-21 is primarily produced by CD4+ T cells, and we find that ILC3s express the receptor for IL-21 (IL-21R). ILC3s are present in IL-21-/- mice, but express higher levels of Tbet. Further, IL-21 signaling upregulates IL-22 and downregulates IL-17A production to promote a protective ILC3 phenotype. Intriguingly, IL-21 acts specifically on this popula-tion of ILC3s as the MHCII-expressing subpopulation is unaffected in IL-21-/- mice. Con-sistent with a protective role for IL-21 in ILC3s, mice deficient in IL-21R exhibit more se-vere disease in a T cell transfer colitis model than mice with intact IL-21R expression. Thus, IL-21 regulation of ILC3s represents a mechanism by which CD4 T cells interact with innate lymphocytes and influence health and disease states.
Recommended Citation
Dulson, Sarah, "Regulation of Intestinal Innate Lymphoid Cells in Acute and Chronic Inflammation" (2019). All ETDs from UAB. 1560.
https://digitalcommons.library.uab.edu/etd-collection/1560