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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Alexander Gevelinger Bastian (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Autoimmune disease is a result of the breakdown in immunological self-tolerance leading \nto destruction of self-tissues mediated by the aberrant immune attack. In Multiple Sclerosis \n(MS), CD4+ T cells mediate destruction of myelin in the central nervous system (CNS) leading to \ndebilitating symptoms in afflicted individuals. MS is the leading cause of non-injury disability in \nyoung adults, impacting nearly 1 million people in the United States alone. As is the case for \nmany autoimmune diseases, there is no cure for MS, highlighting the urgent need for new \ntherapeutic platforms. A therapeutic approach to reestablish self-tolerance is likely to be more \neffective and have less side effects than current treatments, highlighting the importance for \ndeveloping such an approach. At the center of this approach lies CD4+ FOXP3+\nregulatory T \ncells (Tregs), which are a subset of T cells that suppress the immune system and play an integral \nrole in controlling autoimmunity. Therapies aimed at increasing Tregs, especially in a disease targeted manner, have the potential to reestablish self-tolerance and cure autoimmunity.\nAll T cells, including Tregs, must recognize antigen on antigen presenting cells (APCs) \nto perform effector functions. Therefore, targeting an APC niche that supports the development \nof Tregs is an effective approach for development of autoimmune therapeutics. Dendritic cells \n(DCs) are a class of APCs known to support Treg development and function. In this study, we \nshow that agonism of Toll-like receptor 4 (TLR-4) with lipopolysaccharide (LPS) or \nmonophosphoryl Lipid A (MPLA) on DCs leads to a CD25+ MHCIIhigh DC phenotype. We show \nthat the expression of CD25 is unique to DCs and that it binds IL-2 from the environment \nwithout detectable downstream signaling. Importantly, we show that this bound IL-2 can be \nutilized by responder T cells, highlighting a potential function of CD25 on DCs. We then \ncombined TLR-4 agonism with our lab’s DC-targeting tolerogenic vaccine, GMCSF-MOG, \nwhich we have previously shown leads to high levels of Tregs and amelioration of experimental \nautoimmune encephalomyelitis (EAE) in mice. When GMCSF-MOG is combined with MPLA, \nTreg levels are increased and extend out to 78 days post injection. The enhanced and extended \nTreg levels observed when MPLA is included in the vaccine likely play a role in accelerating the \nGMCSF-MOG-mediated amelioration of EAE and preventing observed EAE relapse. At the crux \nof DC-mediated tolerance induction is the efficiency of the antigen recognition event. Lower \naffinity TCR ligation supports tolerance through lower induction of costimulatory molecules \n(CD40L) and increased induction of inhibitory molecules (PD-1). Furthermore, inhibiting the \nCD40L/CD40 axis increases Treg induction. Overall, we show that TLR-4 agonism leads to \nCD25+ 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 \nrecognition events.

Additional Information

Publication

Dissertation

Language: English

Date: 2023

Subjects

tolerogenic adjuvant, CD25+ dendritic cells

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