The activation and fate of Salmonella-specific CD4+ T cells in murine Salmonellosis
Work by us and others over recent years has reaffirmed the importance of CD4+ T cells in immunity against the murine model of invasive Salmonellosis. The C57BL/6 mouse is extremely sensitive to Salmonella Typhimurium (i.v. LD50 <10 bacteria) but the mouse can be vaccinated to immunity using a live-attenuated vaccine known (TAS2010 or BRD509). This immunity is largely conferred through CD4+ T cells. The specificity of the protective T cell response is poorly described, but recent work by Nancy Wang, using peptide eluted from MHC Class II molecules from Salmonella-infected DCs, has revealed novel epitopes that engage much stronger CD4+ T cell recall responses in vaccinated mice, than those for previously-characterised Salmonella epitopes. These earlier epitopes were identified in the bacterial flagellin or the SPI-2 proteins SseI and SseJ. Adrian is currently fine mapping the Wang epitopes. Once the Wang epitope specific 'registers' are established, Adrian will collaborate with the Rossjohn Laboratory (Monash University) to use these epitopes to create novel MHC Class II tetramers to identify Salmonella-specific T cells. These tetramers will return with Adrian to Bonn to assist in studies aimed at tracking the early activation and migration of Salmonella-specific CD4+ T cells in the murine model.In parallel, Nancy and Dick will co-supervise Anna to study the downstream fate of tetramer-marked T cells, building on work of another student in the Strugnell-Bedoui laboratories (Newton Peres), whose data argues for the development of tissue-specific immunity, mediated through CD4+ T cells.
Influence of intestinal migratory DCs on the immune defence against Salmonella infection
Myeloid cells are of major importance for the transmission of invasive Salmonella strains from the intestine to the mesenteric lymph nodes (mLN), as well as liver and spleen. From the mouse model of typhoidal Salmonellosis, which is based on oral infection of mice with Salmonella enterica serovar Typhimurium, it is known that CD103+ migratory dendritic cells (DC) are preferentially infected with Salmonella and migrate to the mLN to induce protective T cell responses. In this project, we would like to bring together the complementary expertise of the Strugnell lab in Salmonellae-driven infection models and of the Förster group in myeloid cell function and migration to study the potential of CCL17+CD103+ intestinal DC to induce potent adaptive immunity to Salmonella. Specifically, we want to explore the ability of the chemokine CCL17 and the proinflammatory cytokine GM-CSF to induce activation and migration of Salmonella infected DC, and study the influence of these mediators on the antigen-presenting function of infected DC. We will use Salmonella vaccine strains expressing the model antigen Ovalbumin to quantify CD4+ and CD8+ T cell responses as well as B cell immunity. Our long-term goal is to employ the newly gained knowledge on the functional relevance of CCL17-expressing DC in Salmonella infection to improve future vaccination strategies.