Dwyer, Gaelen Kathryn
(2021)
Mechanisms underlying IL-33-driven T cell responses in alloimmunity and mucosal injury.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The understanding of the IL-1 family cytokine, interleukin (IL)-33, continues to evolve with our understanding of homeostasis and immunity. In the described studies, I add new mechanistic insight into how IL-33 directs a network of regulatory T cells (Treg) and Type 1 T helper (Th1) cells in mucosal injury and alloimmunity. First, I established that IL-33 acts on Treg expressing the IL-33 receptor, Serum Stimulation-2 (ST2), to mediate the secretion of IL-13 after lung injury. By generating a mouse with Treg deficient for IL-13, I established Treg secreted IL-13, is not involved in direct T cell suppression, but is critical to control lethal inflammation and support early injury responses after lung damage. Treg IL-13 limited the presence of local myeloid populations after injury by acting on monocytes and macrophages to direct their differentiation into Arginase 1+ macrophages that mediate tissue repair. These data identify a new regulatory mechanism involving IL-33 and Treg secretion of IL-13 in response to tissue damage that is instrumental in limiting local inflammatory responses and may shape the myeloid compartment after lung injury. Second, I revealed an unknown function for IL-33 in the activation and differentiation of alloreactive CD4+ T cells after allogeneic hematopoietic cell transplantation. Specifically, I identify that IL-33 is as a stromal cell-derived damage-associated molecular pattern that is released from the recipient and functions as a costimulatory signal driving the activation and differentiation of alloreactive Th1 cells. This mechanism supports CD4+ T cell differentiation into Th1 cells by augmenting TCR signaling pathways and independent of innate cell-derived IL-12. This mechanism is TCR-dependent since IL-33-stimulation of CD4+ T cell is not required for lymphopenia-induced expansion. Together the findings of my graduate studies highlight the importance of IL-33 in CD4+ T cell immunobiology. These studies also support the importance of understanding pleiotropic molecules like IL-33, which is clearly an important molecule that communicates tissue conditions to a variety of immune cells across different pathologies. This knowledge will provide a foundation, allowing for the development of ways to safely and effectively modulate the ST2+ immune cell network to achieved desired outcomes after injury, infection, and malignancy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Dwyer, Gaelen Kathryn | gkd3@pitt.edu | gkd3 | |
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| ETD Committee: |
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| Date: |
24 August 2021 |
| Date Type: |
Publication |
| Defense Date: |
20 July 2021 |
| Approval Date: |
24 August 2021 |
| Submission Date: |
4 August 2021 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
195 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Interleukin-33, acute lung injury, repair, regulatory T cells, graft vs. host disease, Type 1 T helper cells, costimulation |
| Date Deposited: |
25 Aug 2021 01:17 |
| Last Modified: |
24 Aug 2023 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41527 |
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