Chen - T cell immunology
Our lab specialises in CD8+ T cell biology and antigen processing and presentation, especially in relation to the development of cross-protective immune responses to the influenza virus.
Our research activities are divided between human T cell research (identification of mechanisms generating immunodominant human anti-influenza CD8+ T cells and CD8+ T cell epitopes for common HLA molecules expressed within the Australian population) and mouse models of influenza virus infection. These projects investigate the interactions between T cells and antigen-presenting cells, macrophages and monocytes and their impact on the severity of influenza induced lung pathogenesis.
As part of the NHMRC Influenza program (2014-2019), my lab uses our expanding knowledge of innate versus adaptive immune cell interactions and antigen processing, presentation and epitope selection to 1) aid the development of a universal T cell-based vaccine to the influenza virus and 2) elucidate the host immune cell factors governing influenza infection severity.
Investigating the role of defective ribosomal products in influenza induced immune responses
CD8+ T cells eliminate virus infected cells by recognizing small portions of viral proteins, known as peptides, displayed by surface MHC class I molecules. The source of these important peptides remains highly controversial as the rapid presentation of viral peptides often contrasts starkly with the high stability of their source proteins. This has led to the DRiPs (Defective Ribosomal Products) hypothesis of antigen presentation, which posits that errors in transcription, translation and post-translational protein maturation result in synthesis of rapidly degraded peptides that are exploited for immunosurveillance. In particular, although the contribution of translational errors to viral peptide generation has been determined in model systems, the relative contributions of mis-translation to the induction of natural anti-viral TCD8+ responses is still uncertain.
We aim to identify and quantitate the relative contributions of DRiPs-generated peptides to the protective anti-influenza immune response in mice and humans. Our findings have the potential to greatly change the way we identify novel anti-pathogen immune responses, especially for future vaccine development.
External collaborators: Jonathan W. Yewdell and Jack R. Bennink, NIH
Investigating the role of macrophage and monocyte heterogeneity in influenza induced lung pathogenesis
Macrophages and monocytes are part of the early innate immune response to influenza. It is now well-established that residential tissue macrophages exert differential immunoregulatory functions to pro-inflammatory monocytes recruited from the bloodstream. Using a combination of transcriptome studies and targeted genomic engineering, we are now investigating the specific immunoregulatory proteins facilitating macrophage and monocyte mediated immune responses against influenza, with the key goal of identifying new and translatable protective therapeutic targets against influenza infection as well as pathological biomarkers of enhanced disease severity in human patients. As macrophages play a central role in immune cell homeostasis in the lungs, we are also investigating the role of macrophages and monocytes in either enhancing or suppressing anti-influenza CD8 T cell immunity.