The immunodominant influenza matrix t cell epitope recognized in human induces influenza protection in HLA-A2/Kb transgenic mice

Abstract

The protective efficacy of the influenza matrix protein epitope 58-66 (called M1), recognized in the context of human HLA-A2 molecules, was evaluated in a HLA-A2/K(b) transgenic mouse model of lethal influenza infection. Repeated subcutaneous immunizations with M1 increased the percentage of survival. This effect was mediated by T cells since protection was abolished following in vivo depletion of all T lymphocytes, CD8(+), or CD4(+) T cells. The survival correlated with the detection of memory CD8(+) splenocytes able to proliferate in vitro upon stimulation with M1 and to bind M1-loaded HLA-A2 dimers, as well as with M1-specific T cells in the lungs, which were directly cytotoxic to influenza-infected cells following influenza challenge. These results demonstrated for the first time that HLA-A2-restricted cytotoxic T cells specific for the major immunodominant influenza matrix epitope are protective against the infection. They encourage further in vivo evaluation of T cell epitopes recognized in the context of human MHC molecules.

A call to cellular & humoral arms: Enlisting cognate T cell help to develop broad-spectrum vaccines against influenza A

“…Although CTL responses do not alter susceptibility to infection or subsequent infection, 91 they do play a role in the containment of influenza once infection has occurred. 17,92 T-cell responses following infection are known to wane over time. 93 This may be in part a function of natural infection since native viral proteins NS1 and PB2 are known to inhibit the immune response.…”

New technologies for influenza vaccines

“…161 In rodent models, such T cell-based vaccines can protect from challenge. [155][156][157]159,162 In the more rigorous ferret model, they perform less well. 158 The recurrent nature of influenza infection, despite the presence of such conserved antigens in every circulating influenza virus strain, is an indication that immunity directed against these antigens is incomplete, although cell mediated responses appear to contribute to the clearance of infection in humans.…”

“…[155][156][157][158][159][160] Vaccines based solely on conserved internal antigens must rely on cell-mediated immunity, because the target antigens are not exposed on the surface of an influenza virion for antibody binding. 161 In rodent models, such T cell-based vaccines can protect from challenge.…”

Escherichia coliExpressing Recombinant Antigen and Listeriolysin O Stimulate Class I-Restricted CD8+ T Cells following Uptake by Human APC

“…The Ag tested was the amino acid residues 58 -66 epitope of human type A influenza virus matrix protein (M1 protein) that binds to HLA-A2 (15)(16)(17)(18)(19)(20). We observed that T cell stimulation was dependent on LLO coexpression, and also on proteasome activity.…”

“…The epitope is generated in influenza-infected cells and also in DCs after phagocytosis of apoptotic fragments of virusinfected cells (5). Circulating T cells specific for M 58 -66 are detectable in most previously exposed HLA-A2 ϩ individuals as shown by both IFN-␥ ELISPOT and tetrameric MHC-peptide analyses (15,17,19,20). T cells specific for epitope M 58 -66 were generated from a HLA-A2 healthy blood donor as described in Materials and Methods.…”