Podcast 'Aiming for a HIV vaccine'
HLA-E bound to the signal peptide VMAPRTLVL (VL9) (left) and HIV Gag RL9 (right). Crystal structures of each were determined and are overlaid by DAMMI bead models derived from small angle x-ray scatter (SAXS) of the same complexesin solution. The lower affinity peptide RL9 shows a more amorphous low resolution structure in solutions. (Walters et al Cell Reports 2022, in press)
Professor of Molecular Medicine
Classical and Non-Classical T cell responses.
I have studied human T cell immune responses since 1974, with a particular interest in virus specific HLA restricted CD8 T cells. In the 1980s, working with Alain Townsend we found that they recognised peptides bound to HLA molecules. After this early work on influenza, my group worked on HIV-1 for many years studying CD8 T cell responses in early infection and how virus escapes by mutating peptide epitopes, compromising the immune control of the infection. I was involved in vaccine development work and have been a member of the Scientific Leadership Group of the NIAID Center for HIV AIDS Vaccine Development consortium since 2005.
My interest in HLA has included non-classical HLA molecules and their relativesm in particular CD1 and recently the HLA-E. In 1988 Veronique Braud in my group showed that HLA-E bound to a conserved nonamer peptide derived from the signal sequence of classical HLA class I molecules and that this was recognised by the NKG2A/C receptors on natural killer cells, regulating their function. In 2016, we joined a collaboration with Louis Picker and colleagues at OHSU, who had shown that T cells stimulated in rhesus macaques by a cytomegalovirus vectored SIV vaccine are HLA-E restricted. These T cells are able to clear acute SIV infection in approximately 50% of animals after virus challenge. This led us (Geraldine Gillespie, Simon Brackenridge, Lucy Walters, Max Quastel) to explore how HLA-E binds a broad range of peptides, some in an atypical fashion, determining their molecular structures. Using in vitro priming techniques, we (Hongbing Yang, Hong Sun) have been able to demonstrate human CD8 T cells specific for HIV, SARS Coronavirus-2 and self antigenic peptides presented by HLA-E. We are currently working on virus specific and tumour specific HLA-E restricted T cells with an interest in developing immuno-therapies that could be applied universally because of the very limited polymorphism of HLA-E.
Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides.
Yang X. et al, (2022), Nature
Immune signature atlas of vaccines: learning from the good responders.
Pedroza-Pacheco I. and McMichael AJ., (2022), Nature immunology
Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes.
Walters LC. et al, (2022), Cell reports, 39
Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity.
Li D. et al, (2022), Commun Biol, 5
HLA-E–restricted, Gag-specific CD8+ T cells can suppress HIV-1 infection, offering vaccine opportunities
Yang H. et al, (2021), Science Immunology, 6, eabg1703 - eabg1703