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Clin Transl Immunology
. 2026 Aug 2;15(8):e70118.
doi: 10.1002/cti2.70118. eCollection 2026.
CD4+ T-cell responses directed towards A/H5N1-derived haemagglutinin peptides increase in patients with seasonal influenza A virus infection
Lilith F Allen 1 , Louise C Rowntree 1 , Mitchell Jenzen 2 3 , Ruth R Hagen 1 , Nathan P Croft 2 , Fiona James 4 , Genevieve E Martin 1 4 , Anthony W Purcell 2 , Patricia T Illing 2 , Steven Y C Tong 5 6 , Allen C Cheng 7 8 , Tom C Kotsimbos 9 10 , Jason A Trubiano 4 6 11 12 , Katherine Kedzierska 1 13 , Thi H O Nguyen 1
Affiliations
Objectives: Recent outbreak of influenza A/H5N1 viral infections in birds and mammals worldwide prompted renewed concerns over an emerging H5N1-related influenza pandemic in the generally immunologically-naive global population. Cross-reactive CD4+ T cells between A/H1N1 and A/H5N1 subtypes targeting internal and surface influenza proteins have been identified in humans, indicating some protection against severe and fatal A/H5N1 infection.
Methods: To detect T-cell responses towards H1 and H5 viruses, we stimulated PBMCs from patients hospitalised with seasonal influenza A viruses, alongside healthy individuals, with overlapping peptide pools spanning hemagglutinin (HA) and neuraminidase (NA) of A/Vietnam/1203/2004 (H5N1) and A/New York/18/2009 (H1N1-pdm09-like) viruses.
Results: Majority of acutely infected and healthy participants (100% and 75%, respectively) had detectable CD4+ and CD8+ T-cell responses towards H1-HA and H5-HA, whereas 30-80% of individuals had detectable H5-NA responses. H1 and H5 HA-specific CD4+ T-cell responses highly correlated, suggesting some level of cross-reactivity between T-cell responses directed against H1 and H5 subtypes. HA-specific CD4+ T-cell responses were increased in influenza patients compared to healthy participants. We found no differences in H1- and H5-specific T cell responses between those born pre- and post-1968, irrespective of infection status. Sequence alignment of H1 and H5 viruses identified high conservation in the HA2 stalk subunit (81.53%). CD4+ T-cell immunity towards immunodominant HA306-318 epitope, restricted by several HLA-DRB1 molecules, revealed limited cross-reactivity between Group 1 and Group 2 HA-subtypes.
Conclusion: We define correlative H1- and H5-specific CD4+ T-cell responses during seasonal influenza A virus infection, likely reflecting some level of H1/H5 T cell cross-reactivity.
Keywords: CD4+ T cells; H5N1; T cells; immunology; influenza virus; pandemic influenza.
. 2026 Aug 2;15(8):e70118.
doi: 10.1002/cti2.70118. eCollection 2026.
CD4+ T-cell responses directed towards A/H5N1-derived haemagglutinin peptides increase in patients with seasonal influenza A virus infection
Lilith F Allen 1 , Louise C Rowntree 1 , Mitchell Jenzen 2 3 , Ruth R Hagen 1 , Nathan P Croft 2 , Fiona James 4 , Genevieve E Martin 1 4 , Anthony W Purcell 2 , Patricia T Illing 2 , Steven Y C Tong 5 6 , Allen C Cheng 7 8 , Tom C Kotsimbos 9 10 , Jason A Trubiano 4 6 11 12 , Katherine Kedzierska 1 13 , Thi H O Nguyen 1
Affiliations
- PMID: 42544319
- PMCID: PMC13429298
- DOI: 10.1002/cti2.70118
Objectives: Recent outbreak of influenza A/H5N1 viral infections in birds and mammals worldwide prompted renewed concerns over an emerging H5N1-related influenza pandemic in the generally immunologically-naive global population. Cross-reactive CD4+ T cells between A/H1N1 and A/H5N1 subtypes targeting internal and surface influenza proteins have been identified in humans, indicating some protection against severe and fatal A/H5N1 infection.
Methods: To detect T-cell responses towards H1 and H5 viruses, we stimulated PBMCs from patients hospitalised with seasonal influenza A viruses, alongside healthy individuals, with overlapping peptide pools spanning hemagglutinin (HA) and neuraminidase (NA) of A/Vietnam/1203/2004 (H5N1) and A/New York/18/2009 (H1N1-pdm09-like) viruses.
Results: Majority of acutely infected and healthy participants (100% and 75%, respectively) had detectable CD4+ and CD8+ T-cell responses towards H1-HA and H5-HA, whereas 30-80% of individuals had detectable H5-NA responses. H1 and H5 HA-specific CD4+ T-cell responses highly correlated, suggesting some level of cross-reactivity between T-cell responses directed against H1 and H5 subtypes. HA-specific CD4+ T-cell responses were increased in influenza patients compared to healthy participants. We found no differences in H1- and H5-specific T cell responses between those born pre- and post-1968, irrespective of infection status. Sequence alignment of H1 and H5 viruses identified high conservation in the HA2 stalk subunit (81.53%). CD4+ T-cell immunity towards immunodominant HA306-318 epitope, restricted by several HLA-DRB1 molecules, revealed limited cross-reactivity between Group 1 and Group 2 HA-subtypes.
Conclusion: We define correlative H1- and H5-specific CD4+ T-cell responses during seasonal influenza A virus infection, likely reflecting some level of H1/H5 T cell cross-reactivity.
Keywords: CD4+ T cells; H5N1; T cells; immunology; influenza virus; pandemic influenza.