A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation

June 6th, 2024

New study on targeting a single mutation in influenza A virus universal epitope transforms immunogencity and protective immunity led by James Geary, Dr Sarah Curtis, and Dr Bruce MacLachlan is now published online in Cell Reports!

CD4+ T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as

influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules

governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are

less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues

(PFRs), to ‘‘tune’’ CD4+ T cell responses within an in vivo model system of influenza. Using a recombinant

virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited

weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4+ and CD8+ T cells prior to re-infection. Structural

analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in

the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4+ T cell immunity is achievable

with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.

The full paper can be accessed here

Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

July 19, 2023

New study on CD4+ T cell epitopes of SARS-CoV-2 led by Dr Bruce MacLachlan is now published online in Cell Reports!

We define model antigens presented by HLA-DR1 and assess the impact of Spike mutations on T cell recognition. We aimed to provide high resolution epitope information of emerging CD4+ T cell epitopes and thus solved x-ray crystallographic structures of six peptide-HLA-DR1 complexes; 3 Spike and 3 non-Spike (M, nsp3 & nsp14). We could solve complexes of high and low affinity binding peptides and could not correlate peptide affinity with immunogenicity. 

As the pandemic unfolded, we observed Omicron mutations in two of the Spike epitopes we described structurally. Testing in HLA-DR1+ donors who had been vaccinated, we observed that donors could no longer recognise BA.1 Omicron variant forms. 

To understand this we solved further structures of Omicron variant peptide-HLA-DR1 complexes: observing a single amino acid mutation was sufficient to induce a drastic change in a presented epitope through inducing an epitope "register shift”. This effectively creating a "new" epitope to the perspective of T cells. 

This shows that CD4+ T cell memory is finely poised at the level of antigen presentation which is unique to the "open ended" nature of the HLA-II groove.

The full paper can be accessed here

Successful Immunotherapy is Linked to Devlopment of Specialised Blood Vessels in Solid Cancers

December 15th 2022

Applying three-dimensional imaging methods, researcher, Dr Stefan Milutinovic, showed that cancers which are successfully killed by the immune system contain networks of blood vessels which are specialised in their ability to allow immune cells to enter tumours. The work has just been published in Cancer Research Communications.

Prof Awen Gallimore said that the new technology offers the possibility to better understand the co-operation between blood vessels and immune activation and moreover, that the results indicate that targeting blood vessels has the potential to significantly improve the success of the current immunotherapies.

The lab, which is funded by Cancer Research UK, is currently building on this work to find ways of inducing development of these blood vessels in solid cancers.

Read the full paper here.