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Dissertation
Two sides of the same coin: the role of IL-27 in driving pathogenic T cells in a mouse model of Sjögren’s disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007584
Abstract
Sjögren’s disease (SjD) is a chronic autoimmune disease that targets the exocrine glands and is characterized by focal lymphocytic inflammation in lacrimal and salivary glands. An estimated 4 million Americans suffer from SjD, where they experience profound dryness, joint pain, fatigue, other extra-glandular manifestations, and have an increased risk of developing lymphoma. Nonobese diabetic (NOD) mice spontaneously develop SjD-like autoimmunity, including focal inflammation of the glands, dominated initially by T cells.
IL-27 is a heterodimeric protein increased in the saliva and serum of people with SjD. Additionally, IL-27 is required for NOD mice to develop SjD-like autoimmunity. However, the role that IL-27 plays in driving glandular autoimmunity is not fully elucidated. My thesis work here aimed to utilize IL-27 receptor deficient and IL-27 cytokine deficient NOD mice to assess the role of IL-27 in SjD-like autoimmunity.
Here, I defined T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal lacrimal gland inflammation in immunodeficient recipients. Intrinsic IL-27 signaling drives T follicular helper (TFH) cells and CD39hi exhausted CD4 T cells in lacrimal gland disease in NOD mice. Both TFH and CD39hiPD-1hi populations are found in spontaneous disease in NOD mice, and NOD mice deficient in IL-27Rα expression lack both TFH cells and PD-1hiCD39hi CD4 T cells. PD-1hiCD39hi CD4 T cells are exhausted CD4 T cells, with decreased cytokine production compared to other CD4 effector T cells. T cell-intrinsic effects of IL-27 drive CD39hi exhausted CD8 T cells (TEX) and CD73hi precursors of exhausted CD8 T cells (TPEX) in lacrimal gland disease in NOD mice. Both TEX and TPEX populations are found in spontaneous disease in NOD mice and are lacking in NOD mice deficient in IL-27Rα expression. Both TEX and TPEX CD8 T cells have decreased cytokine production compared to effector CD8 T cells, while maintaining cytotoxic potential.
These studies together indicate a role for IL-27 in driving two distinct differentiation states in T cells, that are similar between CD4 effector and CD8 T cells. These observations further highlight the importance for understanding the role of IL-27 as a potential biomarker or therapeutic for people with SjD. Together, this works adds to the growing body of literature that IL-27 drives pathogenic T cells in autoimmunity.
Details
- Title: Subtitle
- Two sides of the same coin: the role of IL-27 in driving pathogenic T cells in a mouse model of Sjögren’s disease
- Creators
- Ivy Lynne Debreceni
- Contributors
- Scott M Lieberman (Advisor)Stanley Perlman (Committee Member)Nitin Karandikar (Committee Member)Ali Jabbari (Committee Member)Ryan Zander (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007584
- Publisher
- University of Iowa
- Number of pages
- xviii, 149 pages
- Copyright
- Copyright 2024 Ivy Lynne Debreceni
- Language
- English
- Date submitted
- 11/25/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 130-149).
- Public Abstract (ETD)
- Sjögren’s disease (SjD) is an autoimmune disease where a person’s immune system attacks their own body, typically including the tear and saliva producing glands. Approximately 4 million Americans suffer from SjD, experiencing profound dryness, joint pain, fatigue, and have an increased risk of cancer. Nonobese diabetic (NOD) mice spontaneously develop SjD-like autoimmunity, including inflammation of the glands similar to human SjD, providing a model to define the early signals driving immune cells to attack these glands. We have found that one signal required for NOD mice to develop SjD-like autoimmunity is interleukin (IL)-27. My thesis work utilized mice deficient in IL-27 signal or receiver to define how IL-27 drives SjD-like autoimmunity in NOD mice. I found that IL-27 is a required signal for T cells (both CD4 and CD8 T cells) to attack the tear-producing glands. Specifically, IL-27 triggers CD4 T cells to become specialized in talking to B cells or to become exhausted where they lose the ability to produce some inflammatory signals. Similarly, when CD8 T cells see IL-27, they become CD8 T cells with the ability to self-renew or they become exhausted. These exhausted CD4 and CD8 T cells retain some inflammatory functions suggesting they may still contribute to gland inflammation. These studies define the role of IL-27 on T cells that attack the tear-producing glands including the effects of IL-27 in driving two distinct pathways paralleled between CD4 and CD8 T cells highlighting the potential utility of IL-27 for future diagnostics or therapeutics in SjD.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9984774868602771
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