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Mechanisms underlying IL-33-driven T cell responses in alloimmunity and mucosal injury

Dwyer, Gaelen Kathryn (2021) Mechanisms underlying IL-33-driven T cell responses in alloimmunity and mucosal injury. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Dwyer, Gaelen Kathryngkd3@pitt.edugkd3
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairThomson, Angus Wthomsonaw@upmc.edu
Thesis AdvisorTurnquist, Heth Rhet5@pitt.edu
Committee MemberPoholek, Amandapoholeka@pitt.edu
Committee MemberVignali, Dario AAdvignali@pitt.edu
Committee MemberShlomchik, Warren Dwarrens@pitt.edu
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: 25 Aug 2021 01:17
URI: http://d-scholarship.pitt.edu/id/eprint/41527

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