Year: 2013
Type: article
Abstract: Cross-presentation is the process by which professional Antigen Presenting Cells (APCs) are able to load peptides from an extracellular processed protein into class I molecules, triggering a CD8+ T cells response. How to increase the efficiency of this process is thus an area of great interest for the development of antitumor and antiviral vaccines which are required to stimulate a cytotoxic T cell response. One promising strategy is the use of adjuvants, molecules that are added to vaccines in order to modulate the immune response and increase protection. The discovery that some compounds with adjuvant function are recognized by Toll like receptors (TLRs), receptors involved in pathogen-associated molecular patterns recognition, drove the interest in developing a novel family of vaccine adjuvant based on triggering the TLR pathways. The aim of my PhD project is to investigate if the novel compound, agonist of TLR2 (SMIP2-1), can enhance cross-presentation of soluble antigens to CD8+ T cells. SMIP2-1 is a novel synthetic lipopeptide, identified through two cell-based high throughput screens performed at the Genomic Institute of Novartis Research Foundation, and is currently under evaluation as vaccine adjuvant by Novartis Vaccines. Using mice reconstituted with Ovalbumin (OVA) specific OT-I TCR transgenic cells, as well as unreconstituted wild type mice, immunized with OVA and SMIP2.1, we found that addition of our compound to the vaccine formulation increases CD8+ T cell proliferation, cytokines production, and cytotoxic activity, along with specific antibody production. Moreover, using an OVA expressing tumor model, we show that the CTLs induced by the SMIP2.1 formulated vaccine are able to inhibit tumor growth in vivo. One mechanism by which SMIP2.1 could enhance the immunogenicity of antigens is its ability to increase antigen deposition in the draining lymph node of the site of injection, and the amount of APC that take up the antigen, as we demonstrated by confocal analysis. We then identified which cells populations can cross-present in vitro and we found that both CD8+ and CD8- DCs are able to cross-present when stimulated with SMIP2.1 In order to evaluate the effect of SMIP2.1 on human cells, we used a flow cytometry assay to detect activation of CD8+ T cells isolated from human PBMC of Cytomegalovirus seropositive donors. We found that stimulation with SMIP2.1 is able to greatly increase the capacity of human APC, pulsed in vitro with the pp65 CMV protein, to activate CMV-specific CD8+ T cells. Over all our data demonstrate that vaccination with exogenous antigen formulated with SMIP2.1 is a successful strategy to induce a cytotoxic T cell response along with antibody production.
Author: Melissa Santone
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2273660753