Harnessing dendritic cells for vaccine development
Dendritic cells (DCs) present exogenous antigens on MHC class I molecules to cytotoxic T lymphocytes via a specialized pathway known as cross presentation. Characterization of this pathway might lead to therapeutic strategies that exploit it to induce immune responses against viruses or cancer, or to prevent autoimmunity. In vivo targeting of antigens to DC surface receptors is a more effective approach in immunotherapy when compared to using ex vivo antigen loaded DCs. However, not all receptors are equally effective at delivering antigens to the cross-presentation pathway. To understand this phenomenon, we are undertaking comparative studies of the endocytic pathway followed by receptors that mediate cross-presentation versus those that do not. Conventionally used microscopic methods are limited in being qualitative and in their inability to study the kinetics of antigen trafficking. Using biochemical methods such as subcellular fractionation and Western blot, we are comparing antigen internalisation, localisation and degradation upon uptake by different DC receptors. We will also characterize the endosomal compartments preferably reached by receptors that favor cross presentation; using label-free quantitative proteomic approaches established in the laboratory (Segura et al, 2010).
This project will reveal which receptors are the most appropriate to target to design more effective vaccines and immunotherapies.
Professor Jose Villadangos
Dr Justine Mintern (University of Melbourne)
Dr Angus Johnston (Monash University)
- Moffat JM, Segura E, Khoury G, Caminschi I, Cameron PU, Lewin SR, Villadangos JA*, Mintern JD*. Targeting antigen to BST-2 expressed by conventional and plasmacytoid dendritic cells elicits efficient antigen presentation. Eur J Immunol 2013; 43: 595-605. * Corresponding authors
- Moffat JM, Cheong WS, Villadangos JA, Mintern JD, Netter HJ. Hepatitis B virus-like particles access major histocompatibility class I and II antigen presentation pathways in primary dendritic cells. Vaccine 2013; 31: 2310-2316.
- Wakim LM, Smith J, Caminschi I, Lahoud MH, Villadangos JS. Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal Immunol 2015; 8:1060-71.
- Reuter A, Panozza SE, Macri C, Dumont C, Li J, Liu H, Segura E, Vega-Ramos J, Gupta N, Caminschi I, Villadangos JA, Johnston APR, Mintern JD. Criteria for dendritic cell receptor selection for efficient antibody-targeted vaccination. J Immunol 2015; 194: 2696-705.
- Mintern JD, Macri C, Villadangos JA. Modulation of antigen presentation by intracellular trafficking. Curr Opin Immunol 2015; 34: 16-21.
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