Show simple item record

dc.contributor.advisorGenco, Caroline A.en_US
dc.contributor.advisorSynder-Cappione, Jenniferen_US
dc.contributor.authorPapadopoulos, Georgeen_US
dc.date.accessioned2019-07-25T14:02:24Z
dc.date.issued2019
dc.identifier.urihttps://hdl.handle.net/2144/36675
dc.description.abstractSeveral Gram-negative bacteria modify their outer most surface structure, lipopolysaccharide (LPS), to evade immune surveillance and survive within the host. Many of these changes occur within the lipid A domain, a region that is recognized by the innate immune system via Toll-like receptor-4 (TLR4). One such pathogen, Porphyromonas gingivalis, orchestrates chronic inflammatory disease by disrupting immune homeostasis. P. gingivalis initially synthesizes a penta-acylated lipid A that functions as a weak TLR4 agonist but displays tetra-acylated forms that are either immunologically silent or TLR4 antagonists. The impact of lipid A modifications on downstream signaling and antigen-specific immunity are unclear. TLR4 signals from the plasma membrane through a MyD88-dependent pathway and intracellularly through a TRIF-dependent pathway. Here we show that expression of immunological silent or antagonistic lipid A enables P. gingivalis to evade TRIF-dependent signaling in dendritic cells (DCs). Evasion of TRIF signaling accelerated antigen degradation and impaired priming of pathogen-specific T cells. In contrast, a P. gingivalis strain expressing agonist lipid A potently activated TRIF signaling and delayed antigen degradation, thereby preserving peptides for optimal T cell activation. We propose that lipid A modifications control the endocytic activity of DCs and the efficiency at which microbe-specific T cells are primed. We next investigated the impact of purified P. gingivalis LPS on innate signaling and antigen presentation. All P. gingivalis LPS species induced a program of DC maturation that allowed for constitutive antigen uptake and cross-presentation. This was independent of TLR4 agonist activity and required CD14, a protein that transports TLR4 to endosomes where TRIF signaling can occur. Agonist LPS induced signaling through both MyD88 and TRIF and elicited T cell priming. Antagonistic LPS potently accelerated CD14 endocytosis and induced TRIF-biased signaling leading to comparable degree of cross-priming. Immunologically silent LPS promoted CD14 endocytosis but failed to activate signaling and induced T cell tolerance. Collectively, our results demonstrate that modification of lipid A structure enables Gram-negative bacteria to direct the host immune system towards tolerance or immunity. We propose that these findings can be harnessed for therapeutic modulation of the immune system to treat a variety of immune-mediated diseases.en_US
dc.language.isoen_US
dc.subjectImmunologyen_US
dc.subjectCross-presentationen_US
dc.subjectDendritic cellsen_US
dc.subjectGram-negative bacteriaen_US
dc.subjectLipopolysaccharideen_US
dc.subjectT cellsen_US
dc.subjectToll-like receptorsen_US
dc.titleModulation of dendritic cell function and T cell immunity by bacterial lipopolysaccharideen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2019-06-14T19:06:20Z
dc.description.embargo2021-06-14T00:00:00Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineMolecular and Translational Medicineen_US
etd.degree.grantorBoston Universityen_US


This item appears in the following Collection(s)

Show simple item record