Despite intense interest in antiviral T cell priming, the routes of virion movement in lymph nodes (LNs) are imperfectly understood. Current models fail to explain how virus-infected cells rapidly appear within the LN interior after viral infection. To better understand virion trafficking in the LN, we determined virion and infected-cell locations after vaccinia and Zika virus administration. Notably, many rapidly infected cells in the LN interior were adjacent to LN conduits. Using confocal and electron microscopy, we clearly visualized virions within conduits. Functionally, CD8 + T cells rapidly and preferentially associated with vaccinia virus-infected cells deeper in the LN, leading to T cell activation in the LN interior. These results reveal that it is possible for even large virions to flow through LN conduits and infect dendritic cells within the T cell zone to prime CD8 + T cells.
Collagen-rich tissues in the cornea exhibit unique and highly organized extracellular matrix ultrastructures, which contribute to its high load-bearing capacity and light transmittance. Corneal collagen fibrils are controlled during development by small leucine-rich proteoglycans (SLRPs) that regulate the fibril diameter and spacing in order to achieve the unique optical transparency. Cyclodextrins (CDs) of varying size and chemical functionality for their ability to regulate collagen assembly during vitrification process are screened in order to create biosynthetic materials that mimic the native cornea structure. Addition of βCD to collagen vitrigels produces materials with aligned fibers and lamellae similar to native cornea, resulting in mechanically robust and transparent materials. Biochemistry analysis revealed that CD interacts with hydrophobic amino acids in collagen to influence assembly and fibril organization. To translate the self-assembled collagen materials for cornea reconstruction, custom molds for gelation and vitrification are engineered to create βCD/Col implants with curvature matching that of the cornea. Acellular βCD/Col materials are implanted in a rabbit partial keratoplasty model with interrupted sutures. The implants demonstrate tissue integration and support re-epithelialization. Therefore, the addition of CD molecules regulates collagen self-assembly and provides a simple process to engineer corneal mimetic substitutes with advanced structural and functional properties.
Biomaterials employed to raise therapeutic immune responses have become a complex and active field. Historically, vaccines have been developed primarily to fight infectious diseases, but recent years have seen the development of immunologically active biomaterials towards an expanding list of non-infectious diseases and conditions including inflammation, autoimmunity, wounds, cancer, and others. This review structures its discussion of these approaches around a progression from single-target strategies to those that engage increasingly complex and multifactorial immune responses. First the targeting of specific individual cytokines is discussed, both in terms of delivering the cytokines or blocking agents, and in terms of active immunotherapies that raise neutralizing immune responses against such single cytokine targets. Next, non-biological complex drugs such as randomized polyamino acid copolymers are discussed in terms of their ability to raise multiple different therapeutic immune responses, particularly in the context of autoimmunity. Last, biologically derived matrices and materials are discussed in terms of their ability to raise complex immune responses in the context of tissue repair. Collectively, these examples reflect the tremendous diversity of existing approaches and the breadth of opportunities that remain for generating therapeutic immune responses using biomaterials.
The current paradigm that subunit vaccines require adjuvants to optimally activate innate immunity implies that increased vaccine reactogenicity will invariably be linked to improved immunogenicity. Countering this paradigm, nanoparticulate vaccines have been reported to act as delivery systems for vaccine antigens and induce immunity without the need for exogenous adjuvants or local inflammation; however, the mechanisms underlying the immunogenicity of nanoparticle vaccines are incompletely identified. Here, we show that antigens displayed on self-assembling nanofiber scaffolds and delivered intranasally are presented by CD103+ and CD11b+ lung dendritic cells that up-regulate CD80 and migrate into the draining lymph node (LN). This was accompanied by a nearly exclusive priming and accumulation of antigen-specific TH17 cells occurring independently in both LN and lung. Thus, self-assembling peptide nanofiber vaccines may represent a novel, needle- and adjuvant-free means of eliciting protective immunity against fungal and bacterial infections at skin and mucosal barrier surfaces.
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