tetano
Editor, Senior Moderator
Cell Rep
. 2024 May 30;43(6):114259.
doi: 10.1016/j.celrep.2024.114259. Online ahead of print. A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4[SUP]+[/SUP] T cell activation
Sarah Hulin-Curtis[SUP] 1 [/SUP], James K Geary[SUP] 2 [/SUP], Bruce J MacLachlan[SUP] 1 [/SUP], Danny M Altmann[SUP] 3 [/SUP], Laury Baillon[SUP] 3 [/SUP], David K Cole[SUP] 1 [/SUP], Alex Greenshields-Watson[SUP] 4 [/SUP], Sophie J Hesketh[SUP] 1 [/SUP], Ian R Humphreys[SUP] 1 [/SUP], Ian M Jones[SUP] 5 [/SUP], Sarah N Lauder[SUP] 1 [/SUP], Georgina H Mason[SUP] 1 [/SUP], Kathryn Smart[SUP] 1 [/SUP], D Oliver Scourfield[SUP] 1 [/SUP], Jake Scott[SUP] 1 [/SUP], Ksenia Sukhova[SUP] 3 [/SUP], Richard J Stanton[SUP] 1 [/SUP], Aaron Wall[SUP] 1 [/SUP], Pierre J Rizkallah[SUP] 1 [/SUP], Wendy S Barclay[SUP] 3 [/SUP], Awen Gallimore[SUP] 1 [/SUP], Andrew Godkin[SUP] 6 [/SUP]
Affiliations
CD4[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] and CD8[SUP]+[/SUP] T cells prior to re-infection. Structural analysis of the ternary TCR
HLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4[SUP]+[/SUP] T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.
Keywords: CD4(+) T cell; CP: Immunology; HLA-DR1; influenza A virus; lung CD8(+) tissue-resident memory T cell; peptide-flanking residues; vaccine.
. 2024 May 30;43(6):114259.
doi: 10.1016/j.celrep.2024.114259. Online ahead of print. A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4[SUP]+[/SUP] T cell activation
Sarah Hulin-Curtis[SUP] 1 [/SUP], James K Geary[SUP] 2 [/SUP], Bruce J MacLachlan[SUP] 1 [/SUP], Danny M Altmann[SUP] 3 [/SUP], Laury Baillon[SUP] 3 [/SUP], David K Cole[SUP] 1 [/SUP], Alex Greenshields-Watson[SUP] 4 [/SUP], Sophie J Hesketh[SUP] 1 [/SUP], Ian R Humphreys[SUP] 1 [/SUP], Ian M Jones[SUP] 5 [/SUP], Sarah N Lauder[SUP] 1 [/SUP], Georgina H Mason[SUP] 1 [/SUP], Kathryn Smart[SUP] 1 [/SUP], D Oliver Scourfield[SUP] 1 [/SUP], Jake Scott[SUP] 1 [/SUP], Ksenia Sukhova[SUP] 3 [/SUP], Richard J Stanton[SUP] 1 [/SUP], Aaron Wall[SUP] 1 [/SUP], Pierre J Rizkallah[SUP] 1 [/SUP], Wendy S Barclay[SUP] 3 [/SUP], Awen Gallimore[SUP] 1 [/SUP], Andrew Godkin[SUP] 6 [/SUP]
Affiliations
- PMID: 38819988
- DOI: 10.1016/j.celrep.2024.114259
CD4[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] and CD8[SUP]+[/SUP] T cells prior to re-infection. Structural analysis of the ternary TCR
HLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4[SUP]+[/SUP] T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.Keywords: CD4(+) T cell; CP: Immunology; HLA-DR1; influenza A virus; lung CD8(+) tissue-resident memory T cell; peptide-flanking residues; vaccine.