CD4+ T cells recognize unique and conserved 2009 H1N1 influenza hemagglutinin epitopes after natural infection and vaccination

Int Immunol. 2013 Aug;25(8):447-57. doi: 10.1093/intimm/dxt005. Epub 2013 Mar 22.


Influenza A/California/4/2009 (H1N1/09) is a recently emerged influenza virus capable of causing serious illness or death in otherwise healthy individuals. Serious outcomes were most common in young adults and children, suggesting that pre-existing heterologous immunity may influence the severity of infection. Using tetramers, we identified CD4(+) T-cell epitopes within H1N1/09 hemagglutinin (HA) that share extensive homology with seasonal influenza and epitopes that are unique to H1N1/09 HA. Ex vivo tetramer staining revealed that T cells specific for conserved epitopes were detectable within the memory compartment, whereas T cells specific for unique epitopes were naive and infrequent prior to infection or vaccination. Following infection, the frequencies of T cells specific for unique epitopes were 11-fold higher, reaching levels comparable to those of T cells specific for immunodominant epitopes. In contrast, the frequencies of T cells specific for conserved epitopes were only 2- to 3-fold higher following infection. In general, H1HA-reactive T cells exhibited a memory phenotype, expressed CXCR3 and secreted IFN-γ, indicating a predominantly Th1-polarized response. A similar Th1 response was seen in vaccinated subjects, but the expansion of T cells specific for HA epitopes was comparatively modest after vaccination. Our findings indicate that CD4(+) T cells recognize both strain-specific and conserved epitopes within the influenza HA protein and suggest that naive T cells specific for HA epitopes undergo significant expansion, whereas memory T cells specific for the conserved epitopes undergo more restrained expansion.

Keywords: HLA; ex vivo; naive; peptide; tetramer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • Epitopes / immunology*
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Humans
  • Influenza Vaccines / administration & dosage
  • Influenza Vaccines / immunology*
  • Influenza, Human / immunology*
  • Influenza, Human / virology*
  • Middle Aged
  • Vaccination


  • Epitopes
  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Influenza Vaccines