Dataset Information

Self-Assembly of Immune Signals Improves Codelivery to Antigen Presenting Cells and Accelerates Signal Internalization, Processing Kinetics, and Immune Activation.

ABSTRACT: Vaccines and immunotherapies that elicit specific types of immune responses offer transformative potential to tackle disease. The mechanisms governing the processing of immune signals-events that determine the type of response generated-are incredibly complex. Understanding these processes would inform more rational vaccine design by linking carrier properties, processing mechanisms, and relevant timescales to specific impacts on immune response. This goal is pursued using nanostructured materials-termed immune polyelectrolyte multilayers-built entirely from antigens and stimulatory toll-like receptors agonists (TLRas). This simplicity allows isolation and quantification of the rates and mechanisms of intracellular signal processing, and the link to activation of distinct immune pathways. Each vaccine component is internalized in a colocalized manner through energy-dependent caveolae-mediated endocytosis. This process results in trafficking through endosome/lysosome pathways and stimulation of TLRs expressed on endosomes/lysosomes. The maximum rates for these events occur within 4 h, but are detectable in minutes, ultimately driving downstream proimmune functions. Interestingly, these uptake, processing, and activation kinetics are significantly faster for TLRas in particulate form compared with free TLRa. Our findings provide insight into specific mechanisms by which particulate vaccines enhance initiation of immune response, and highlight quantitative strategies to assess other carrier technologies.

SUBMITTER: Bookstaver ML

PROVIDER: S-EPMC6252008 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Self-Assembly of Immune Signals Improves Codelivery to Antigen Presenting Cells and Accelerates Signal Internalization, Processing Kinetics, and Immune Activation.

Bookstaver Michelle L ML Hess Krystina L KL Jewell Christopher M CM

Small (Weinheim an der Bergstrasse, Germany) 20180826 38

Vaccines and immunotherapies that elicit specific types of immune responses offer transformative potential to tackle disease. The mechanisms governing the processing of immune signals-events that determine the type of response generated-are incredibly complex. Understanding these processes would inform more rational vaccine design by linking carrier properties, processing mechanisms, and relevant timescales to specific impacts on immune response. This goal is pursued using nanostructured materia ...[more]

PMID: 30146797

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Project description:Lactoferrin (LF), a key element in mammalian immune system, plays pivotal roles in host defence against infection and excessive inflammation. Its protective effects range from direct antimicrobial activities against a large panel of microbes, including bacteria, viruses, fungi and parasites, to antinflammatory and anticancer activities. In this study, we show that monocyte-derived dendritic cells (MD-DCs) generated in the presence of bovine LF (bLF) fail to undergo activation by up-modulating CD83, co-stimulatory and major histocompatibility complex molecules, and cytokine/chemokine secretion. Moreover, these cells are weak activators of T cell proliferation and retain antigen uptake activity. Consistent with an impaired maturation, bLF-MD-DC primed T lymphocytes exhibit a functional unresponsiveness characterized by reduced expression of CD154 and impaired expression of IFN-? and IL-2. The observed imunosuppressive effects correlate with an increased expression of molecules with negative regulatory functions (i.e. immunoglobulin-like transcript 3 and programmed death ligand 1), indoleamine 2,3-dioxygenase, and suppressor of cytokine signaling-3. Interestingly, bLF-MD-DCs produce IL-6 and exhibit constitutive signal transducer and activator of transcription 3 activation. Conversely, bLF exposure of already differentiated MD-DCs completely fails to induce IL-6, and partially inhibits Toll-like receptor (TLR) agonist-induced activation. Cell-specific differences in bLF internalization likely account for the distinct response elicited by bLF in monocytes versus immature DCs, providing a mechanistic base for its multiple effects. These results indicate that bLF exerts a potent anti-inflammatory activity by skewing monocyte differentiation into DCs with impaired capacity to undergo activation and to promote Th1 responses. Overall, these bLF-mediated effects may represent a strategy to block excessive DC activation upon TLR-induced inflammation, adding further evidence for a critical role of bLF in directing host immune function.

Dataset Information

Self-Assembly of Immune Signals Improves Codelivery to Antigen Presenting Cells and Accelerates Signal Internalization, Processing Kinetics, and Immune Activation.

Publications

Self-Assembly of Immune Signals Improves Codelivery to Antigen Presenting Cells and Accelerates Signal Internalization, Processing Kinetics, and Immune Activation.

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