Abstract
Inducing T cell responses by therapeutic vaccination requires appropriate activation of antigen presenting cells (APCs). The use of virus-like particles (VLPs) containing Toll-like receptor (TLR) ligands has demonstrated remarkable potential in activating APCs and modulating the immune response both for prophylactic vaccines as well as immunotherapy. Here, we employed VLPs associated to TLR ligands as tools to modulate cytotoxic response mediated by CD8+ T cells and provide further insight in the development of T cell-based immunotherapy. We have investigated the in vivo transcriptional signature in dendritic cells (DCs) from mice immunized with VLPs containing distinct classes of nucleic acid and correlated the expression patterns with the efficiency of induced T cell responses. We identified key pathways activated in DCs that are involved in the appropriated induction of T cell responses and show evidence for the modulatory effect of CCL2 in CD8+ T cells responses. These insights shed light on immune networks that are pivotal for the induction of potent cytotoxic T cell responses and identify key genes for appropriate DC activation and subsequent modulation of the adaptive immune response.
Highlights
In spite of all prophylactic vaccines in use to date promoting protection through neutralizing antibodies, there is a growing interest in developing vaccines that induce protection mediated by T cells
We have previously demonstrated that virus-like particles (VLPs) containing B type CpG are able to induce protective T cell responses in tumor models caused by human papilloma virus (HPV) [8] and viral infections [9] while its VLP counterparts containing RNA were unable to provide protection against tumor growth and associated mortality
To compare the ability of Qβ(G10) and Qβ(1668) to induce T cell responses, VLPs were cross-linked with the immunodominant model peptide p33, derived from Lymphocytic Choriomeningitis virus (LCMV)
Summary
In spite of all prophylactic vaccines in use to date promoting protection through neutralizing antibodies, there is a growing interest in developing vaccines that induce protection mediated by T cells. Unlike some vaccines that induce neutralizing antibody responses and have been developed empirically, induction of effective antigen-specific T cell responses has proved itself a complex endeavor that will require major developmental strides before reaching the market [4]. Considering the distinct regulation and complexity of the activation events for B and T lymphocytes, it is reasonable to assume that unlike B cell inducing vaccines, attempts to develop T cell inducing vaccines will not be successful until we have a better understanding of the regulatory networks of T cell responses. Understanding the factors that drive appropriate activation of APCs that correlate to the adaptive response becomes paramount for vaccine development, especially when aiming for T cell mediated protection
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