Dissertation
Myelin-reactive CD8+ T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007900
Abstract
Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4+ T cells, primarily Th1 and Th17 subsets, drive disease pathogenesis, the exact function of CD8+ T cells remains unclear. We previously demonstrated that adoptively transferred myelin-reactive CD8+ T cells (PLP-CD8) prevent EAE induction and suppress ongoing disease by engaging MHC Class-I in recipient mice. In my dissertation, I show that PLP-CD8 induce regulatory changes in both subsets of conventional dendritic cells (cDC1 and cDC2) in the spleens of the recipient mice in vivo and in vitro. Adoptively transferred PLP-CD8 promoted both cDC subsets to upregulate costimulatory and regulatory markers reflecting a mature and regulatory phenotype with an anti-inflammatory cytokine profile and a reduced capacity to support CD4+ T cell proliferation. In vitro, PLP-CD8 induced similar phenotypic changes in both cDC subsets in an antigen-specific, dose-dependent manner. PLP-CD8 directly interacted with cDC1 and indirectly influenced cDC2 through paracrine signaling. Notably, direct interaction with PLP-CD8 had detrimental effects on cDC2. However, the supernatant from this direct interaction did not cause similar changes in cDC2 and rather promoted a mature, regulatory profile reinforcing a contact-dependent negative effect of PLP-CD8 on cDC2. Single-cell RNA sequencing revealed upregulation of key immunoregulatory genes, such as Cd274 (PD-L1), Cd83, Mtor, Tgfb1 (TGF-β1) and Foxo3 with enrichment of immunoregulatory KEGG pathways predominantly in cDC2 but also in the cDC1 subset influenced by PLP-CD8. Our study highlights a novel mechanism in which myelin-reactive CD8+ T cells directly interact with cDC1 and modulate cDC2 through paracrine mechanisms to induce mature, regulatory dendritic cells, which leads to inhibited CD4+ T cell responses and reduced EAE pathogenesis.
Details
- Title: Subtitle
- Myelin-reactive CD8+ T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis
- Creators
- Mohit A. Upadhye
- Contributors
- Nitin J. Karandikar (Advisor)John Harty (Committee Member)Ashutosh Mangalam (Committee Member)Ali Jabbari (Committee Member)Scott Lieberman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Experimental Pathology)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007900
- Publisher
- University of Iowa
- Number of pages
- xv, 171 pages
- Copyright
- Copyright 2025 Mohit A. Upadhye
- Language
- English
- Date submitted
- 04/29/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 161-171).
- Public Abstract (ETD)
The immune system maintains a delicate balance to prevent harmful reactions against the body’s own tissues, a process crucial for maintaining health and preventing autoimmune diseases. When this balance is disrupted, the immune system can attack self-antigens, leading to autoimmune diseases such as Multiple Sclerosis (MS). MS is a debilitating condition where immune cells, primarily T cells, target and destroy the myelin sheath surrounding nerve fibers in the central nervous system (CNS). This destruction results in demyelination, neurodegeneration, and significant disability, affecting approximately 2.3 million people worldwide, with a higher prevalence in females and a young age of onset. Current treatments focus on suppressing the immune system but carry the risk of infections and other complications, and do not offer a cure. Our research has previously identified a unique subset of CD8+ T cells with the ability to regulate the immune response and protect against experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. However, the underlying mechanisms by which these regulatory CD8+ T cells exert their protective effects remain unclear. A thorough understanding of these immunoregulatory mechanisms will be enable us to develop novel targeted therapies for autoimmune diseases such as MS.
In my dissertation, I have explored the interaction between these CD8+ T cells and dendritic cells (DC), key immune cells responsible for sensing and responding to antigens. DC orchestrate immune responses and play a critical role in preventing autoimmunity by maintaining immune tolerance. My findings demonstrate that the regulatory CD8+ T cells influence DC to adopt an immunoregulatory phenotype, thereby suppressing autoimmune responses. By investigating specific subsets of DC, I have elucidated the mechanisms through which CD8+ cells modulate DC function. This work provides novel insights into the interplay between CD8+ T cells and DC and offers a potential avenue for developing targeted therapies for MS.
- Academic Unit
- Pathology
- Record Identifier
- 9984830725802771
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