In 2009, the outbreak of a new swine-origin strain of influenza A H1N1 caused widespread human infection [1
]. One of the most important surface proteins, hemagglutinin (HA) permits the virus to bind to cell membrane and infect the cells. Since mutations enable the virus to escape from either T cell or antibody recognition, current flu vaccines were not effective against the emerging virus. Sequence analyses showed that the HA sequence of the pandemic 2009-H1N1 underwent an antigenic shift [2
] that altered its antigenicity in context of the seasonal flu vaccine.
The antigenicity of HA 2009-H1N1 remained highly conserved to pandemic 1918-H1N1 and partially conserved to seasonal flu strains of the 1930s. Therefore, the majority of infected individuals who were vaccinated with the WHO recommended seasonal flu vaccine did not produce neutralizing antibodies against the new influenza strain. However, elderly and individuals born before 1950 were less affected than expected. The lower infection rate of these age groups has been interpreted as the results of cross-reactive T cells [3
] and antibody [4
] responses to the pandemic 1918-H1N1 and partially cross-reactive T cell response to seasonal flu strains of the 1930s. A study by Boon et al.
] on CD8+
T cell recognition of heterosubtypic H1N1 variants indicated that repeated infection with heterologous viruses may increase cross-reactive Cytotoxic T Lymphocytes (CTL) and thus confer protection against newly emerging strains in absence of a cross-reactive antibody response. Further support for this concept comes from a study of subjects who were vaccinated against seasonal influenza and showed in vitro
cross-reactive T cell responses against HA of the pandemic 2009-H1N1 [6
In growing recognition of the role of T cell responses to H1N1, several groups conducted large-scale Human leukocyte antigen (HLA) binding motif scanning analyses of pandemic and seasonal strains to predict and identify conserved peptides that elicit cross-reactive HLA class I and/or class II restricted T cell responses [7
]. While the affinity-based approach allows a broad coverage of HLA supertypes and epitope bindings [7
], structural approach gives better insight view onto T cell recognition of the HLA-restricted T cell epitopes [10
]. In our study, we are interested in immunogenicity that depends on the quality of T-cell receptor (TCR) interaction with the HLA/peptide complexes rather than HLA-binding peptide affinity only. We, therefore, combined affinity-based epitope prediction with molecular docking to generate conserved high confidence HA T cell epitope candidates of current and past pandemic strains, and consequently analyzed the potential TCR cross-recognition of 2009-H1N1 and 2004-H5N1.
According to Archbold et al.
complex of DM1-TCR and HLA-B*4405/peptide showed significant enhancement in T cell-mediated responses among micropolymorphisms in the HLA-B*44 family, and as such they are key factors in controlling persistent viral infections [12
]. Thus, to perform the experiments we used HLA-B*4405 and DM1-TCR as models. Results of structural models of TCR cross-recognition between 2009-H1N1 and 2004-H5N1 revealed steric and topological effects of TCR contact residue mutations on TCR binding affinity. While these results are novel with respect to HLA-B*4405-restricted H1N1 HA epitopes and DM1-TCR, yet with limited available structural data upon the TCR repertoire, more investigations and experimental analyses are still recommended for further broad perspective of their utility in vaccine development against the emerging virus strains.