Finding new T cell targets for respiratory pathogens

Abstract

Current influenza vaccines generate predominantly antibody-based immune responses against the surface glycoproteins of the included strains and are reformulated annually to match the strains predicted to circulate in the upcoming influenza season. These glycoproteins can differ greatly between strains, limiting vaccine cross-strain protection and efficacy against newly emerged strains.

In contrast, CD8⁺ T cells are activated by virus-derived peptides displayed by HLA class I molecules (HLA-I) on the surface of infected cells. These peptides are generated by the degradation of viral proteins within the cell, allowing display of peptides from conserved internal proteins of the virus, and creating the capacity for cross-strain protective T cell responses. To identify viral peptides with the potential to stimulate CD8⁺ T cell responses, we apply a mass spectrometry-based epitope discovery workflow to characterise peptides naturally presented by HLA-I of infected cells, followed by in vitro immunogenicity screening. This workflow has successfully identified influenza T cell epitopes presented by a range of HLA-I variants. Moreover, we have applied this technology to SARS-CoV-2, identifying post-translationally modified SARS-CoV-2 peptides that stimulate T cell responses. These studies show the power of this workflow for defining immune targets, especially those less easily predicted from the native viral protein sequences.

Biography

Dr Illing is a Group Leader at the Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology at Monash University. Her work focusses on understanding peptide and small molecule presentation to T cells by Human Leukocyte Antigen (HLA), and HLA-like, molecules in the context of infection, drug-hypersensitivity, and cancer.

She received her PhD in 2014 from the University of Melbourne where she investigated the mechanisms underlying abacavir hypersensitivity syndrome, an adverse drug reaction triggered by interactions of the antiretroviral abacavir with a specific HLA variant, HLA-B*57:01. In 2014, she commenced a NHMRC Peter Doherty Early Career Fellowship, continuing her work in the area of drug hypersensitivity in the laboratory of Professor Tony Purcell at Monash University, integrating proteomics, immunopeptidomics and functional immunology to dissect these reactions. Here, her research program has expanded to encompass the interplay between genetic factors (HLA polymorphisms, antigen processing machinery) and environmental factors (therapeutic drugs, influenza infection) in peptide presentation by HLA molecules. In 2021 she was appointed as a BDI Group Leader, continuing to investigate new targets in T cell mediated immunity and their biogenesis.