Targeting Receptors on Antigen Presenting Cells for Effective Vaccination

The design and development of future vaccines against infectious diseases will increasingly depend on detailed knowledge of interactions of microbial components with cells of the immune system. Vaccines have been very successful to induce circulating antibodies that block numerous invasive infectious pathogens, but less successful to induce effector T cells and other cells that counteract intracellular pathogens or cancers. Induction of effector T cells depends on specific pathways of antigen presentation and separate activation signals, usually associated with infection of antigen presenting cells with viral or bacterial pathogens. Vaccines comprising purified proteins are usually manufactured with particulate adjuvants which are thought to be taken up by antigen presenting cells by fluid phase pinocytosis, resulting in antigen presentation that favors the development of helper T cells, avoiding the cellular pathways responsible for development of effector T cells. Adaptive immune responses are induced when antigen presenting cells, including dendritic cells (DCs), encounter antigens in the peripheral tissue. After antigen uptake, DCs migrate toward draining lymph nodes, where peptides associated with class I or class II MHC activate antigen-specific T cells. Peptides loaded onto MHC II molecules can lead to the activation of antigen-specific CD4+ T helper cells, peptide loading onto MHCI can activate antigen-specific cytotoxic CD8+ T cells. Although the intracellular processes for antigen presentation are highly specific, vaccines themselves are not designed for specificity to address antigen processing pathways. Vaccines that favor the development of CD8+ cytotoxic T cells are needed to address circulating intracellular pathogens like TB, and to address future pandemics.



The mechanisms of vaccine antigen sensing by APCs and subsequent modulation of the immune system are still not well characterized. Largely, the mechanism of antigen uptake is attributable to bulk fluid pinocytotic uptake, followed by antigen processing. Further, the involvement of specific receptors on antigen presenting cells to protein or peptide components of vaccines is underexplored. For example, it is now known that hepatitis B surface antigen in the context of the whole viruses during infection can interact with C-type lectin receptors on dendritic cells, implying that those receptors are involved in the uptake of HBsAg adsorbed to aluminum adjuvant present in the human hepatitis B vaccine. Therefore, because these receptors are also activating, the uptake of vaccine particles through binding to C-type lectin receptors also is expected to activate in addition to any action of the aluminum adjuvant. Major advancement in the understanding of the class of toll-like receptors have led recently to the development of adjuvants tailored to activation pathways and alternatives to the use of aluminum salts in human vaccines. The goal of this topic is to explore recent advances in targeting antigen presenting cells with agents/technologies that are aimed modulate specific receptors on antigen presenting cells, especially conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). Most of the strategies to direct antigens to APCs have centered around antigens that are covalently coupled to antibodies that would target activating or inhibitory Fcγ receptors, or to antibodies for certain C type lectin receptors (e.g. anti-DEC205). Other receptors could be used as targets for high affinity interactions with vaccine antigens.



This Research Topic solicits review articles on the status of vaccine development using antigen cell targeting technology. For example, the status of animal and human studies that may have been completed or envisioned that examine the immunogenicity and safety of vaccines that are based on conjugates with antibodies to C-type lectin receptors, Fcγ receptors or other known receptors that are known to active or inhibit activation. The action of vaccines can be directed at viral, bacterial or cancer vaccines, with an emphasis on induction of cytotoxic T cells responses and other cellular mechanisms of cytotoxicity. This research topic also solicits primary research on the structured and distribution of receptors on antigen presenting cells and their possible roles if not previously characterized. This topic also solicits recent information on adjuvants that could be used in concert with targeting technology, assuming that antigen uptake and activation of antigen-presenting cells may occur in the same cell.