TLR-4 agonism induces CD25+ MHCIIhigh dendritic cells in association with tolerogenic antigen recognition

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dc.contributor.advisorMannie, Mark D
dc.contributor.authorBastian, Alexander
dc.contributor.committeeMemberMeher, Akshaya K
dc.contributor.committeeMemberColeman, James P
dc.contributor.committeeMemberDeWitt, Jamie C
dc.contributor.committeeMemberRoop, R. Martin
dc.contributor.committeeMemberGarcia, Brandon L
dc.contributor.departmentMicrobiology and Immunology
dc.date.accessioned2023-02-10T18:42:21Z
dc.date.available2024-02-09T09:01:59Z
dc.date.created2022-12
dc.date.issued2022-12-06
dc.date.submittedDecember 2022
dc.date.updated2023-01-31T21:14:35Z
dc.degree.departmentMicrobiology and Immunology
dc.degree.disciplinePHD-Microbiology & Immunology
dc.degree.grantorEast Carolina University
dc.degree.levelDoctoral
dc.degree.namePh.D.
dc.description.abstractAutoimmune disease is a result of the breakdown in immunological self-tolerance leading to destruction of self-tissues mediated by the aberrant immune attack. In Multiple Sclerosis (MS), CD4+ T cells mediate destruction of myelin in the central nervous system (CNS) leading to debilitating symptoms in afflicted individuals. MS is the leading cause of non-injury disability in young adults, impacting nearly 1 million people in the United States alone. As is the case for many autoimmune diseases, there is no cure for MS, highlighting the urgent need for new therapeutic platforms. A therapeutic approach to reestablish self-tolerance is likely to be more effective and have less side effects than current treatments, highlighting the importance for developing such an approach. At the center of this approach lies CD4+ FOXP3+regulatory T cells (Tregs), which are a subset of T cells that suppress the immune system and play an integral role in controlling autoimmunity. Therapies aimed at increasing Tregs, especially in a disease targeted manner, have the potential to reestablish self-tolerance and cure autoimmunity.All T cells, including Tregs, must recognize antigen on antigen presenting cells (APCs) to perform effector functions. Therefore, targeting an APC niche that supports the development of Tregs is an effective approach for development of autoimmune therapeutics. Dendritic cells (DCs) are a class of APCs known to support Treg development and function. In this study, we show that agonism of Toll-like receptor 4 (TLR-4) with lipopolysaccharide (LPS) or monophosphoryl Lipid A (MPLA) on DCs leads to a CD25⁺ MHCIIhigh DC phenotype. We show that the expression of CD25 is unique to DCs and that it binds IL-2 from the environment without detectable downstream signaling. Importantly, we show that this bound IL-2 can be utilized by responder T cells, highlighting a potential function of CD25 on DCs. We then combined TLR-4 agonism with our lab's DC-targeting tolerogenic vaccine, GMCSF-MOG, which we have previously shown leads to high levels of Tregs and amelioration of experimental autoimmune encephalomyelitis (EAE) in mice. When GMCSF-MOG is combined with MPLA, Treg levels are increased and extend out to 78 days post injection. The enhanced and extended Treg levels observed when MPLA is included in the vaccine likely play a role in accelerating the GMCSF-MOG-mediated amelioration of EAE and preventing observed EAE relapse. At the crux of DC-mediated tolerance induction is the efficiency of the antigen recognition event. Lower affinity TCR ligation supports tolerance through lower induction of costimulatory molecules (CD40L) and increased induction of inhibitory molecules (PD-1). Furthermore, inhibiting the CD40L/CD40 axis increases Treg induction. Overall, we show that TLR-4 agonism leads to CD25⁺ MHCIIhigh DCs and functions as a tolerogenic adjuvant when combined with the DC targeting GMSCF-MOG vaccine through support of low-efficiency Treg-favorable antigen recognition events.
dc.embargo.lift2023-12-01
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10342/12265
dc.language.isoen
dc.publisherEast Carolina University
dc.subjectCD25+ dendritic cells
dc.subjecttolerogenic adjuvant
dc.subject.meshToll-Like Receptor 4
dc.subject.meshDendritic Cells
dc.subject.meshT-Lymphocytes, Regulatory
dc.subject.meshLymphocyte Activation
dc.titleTLR-4 agonism induces CD25+ MHCIIhigh dendritic cells in association with tolerogenic antigen recognition
dc.typeDoctoral Dissertation
dc.type.materialtext

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