tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2015 Feb 2. pii: 201423482. [Epub ahead of print]
[h=1]Physical detection of influenza A epitopes identifies a stealth subset on human lung epithelium evading natural CD8 immunity.[/h] Keskin DB[SUP]1[/SUP], Reinhold BB[SUP]1[/SUP], Zhang GL[SUP]2[/SUP], Ivanov AR[SUP]3[/SUP], Karger BL[SUP]3[/SUP], Reinherz EL[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Vaccines eliciting immunity against influenza A viruses (IAVs) are currently antibody-based with hemagglutinin-directed antibody titer the only universally accepted immune correlate of protection. To investigate the disconnection between observed CD8 T-cell responses and immunity to IAV, we used a Poisson liquid chromatography data-independent acquisition MS method to physically detect PR8/34 (H1N1), X31 (H3N2), and Victoria/75 (H3N2) epitopes bound to HLA-A*02:01 on human epithelial cells following in vitro infection. Among 32 PR8 peptides (8-10mers) with predicted IC[SUB]50[/SUB] < 60 nM, 9 were present, whereas 23 were absent. At 18 h postinfection, epitope copies per cell varied from a low of 0.5 for M1[SUB]3-11[/SUB] to a high of >500 for M1[SUB]58-66[/SUB] with PA, HA, PB1, PB2, and NA epitopes also detected. However, aside from M1[SUB]58-66[/SUB], natural CD8 memory responses against conserved presented epitopes were either absent or only weakly observed by blood Elispot. Moreover, the functional avidities of the immunodominant M1[SUB]58-66[/SUB]/HLA-A*02:01-specific T cells were so poor as to be unable to effectively recognize infected human epithelium. Analysis of T-cell responses to primary PR8 infection in HLA-A*02:01 transgenic B6 mice underscores the poor avidity of T cells recognizing M1[SUB]58-66[/SUB]. By maintaining high levels of surface expression of this epitope on epithelial and dendritic cells, the virus exploits the combination of immunodominance and functional inadequacy to evade HLA-A*02:01-restricted T-cell immunity. A rational approach to CD8 vaccines must characterize processing and presentation of pathogen-derived epitopes as well as resultant immune responses. Correspondingly, vaccines may be directed against "stealth" epitopes, overriding viral chicanery.
[h=4]KEYWORDS:[/h] T-cell avidity; T-cell epitopes; antigen presentation; influenza A viruses; mass spectrometry
PMID: 25646416 [PubMed - as supplied by publisher]
[h=1]Physical detection of influenza A epitopes identifies a stealth subset on human lung epithelium evading natural CD8 immunity.[/h] Keskin DB[SUP]1[/SUP], Reinhold BB[SUP]1[/SUP], Zhang GL[SUP]2[/SUP], Ivanov AR[SUP]3[/SUP], Karger BL[SUP]3[/SUP], Reinherz EL[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Vaccines eliciting immunity against influenza A viruses (IAVs) are currently antibody-based with hemagglutinin-directed antibody titer the only universally accepted immune correlate of protection. To investigate the disconnection between observed CD8 T-cell responses and immunity to IAV, we used a Poisson liquid chromatography data-independent acquisition MS method to physically detect PR8/34 (H1N1), X31 (H3N2), and Victoria/75 (H3N2) epitopes bound to HLA-A*02:01 on human epithelial cells following in vitro infection. Among 32 PR8 peptides (8-10mers) with predicted IC[SUB]50[/SUB] < 60 nM, 9 were present, whereas 23 were absent. At 18 h postinfection, epitope copies per cell varied from a low of 0.5 for M1[SUB]3-11[/SUB] to a high of >500 for M1[SUB]58-66[/SUB] with PA, HA, PB1, PB2, and NA epitopes also detected. However, aside from M1[SUB]58-66[/SUB], natural CD8 memory responses against conserved presented epitopes were either absent or only weakly observed by blood Elispot. Moreover, the functional avidities of the immunodominant M1[SUB]58-66[/SUB]/HLA-A*02:01-specific T cells were so poor as to be unable to effectively recognize infected human epithelium. Analysis of T-cell responses to primary PR8 infection in HLA-A*02:01 transgenic B6 mice underscores the poor avidity of T cells recognizing M1[SUB]58-66[/SUB]. By maintaining high levels of surface expression of this epitope on epithelial and dendritic cells, the virus exploits the combination of immunodominance and functional inadequacy to evade HLA-A*02:01-restricted T-cell immunity. A rational approach to CD8 vaccines must characterize processing and presentation of pathogen-derived epitopes as well as resultant immune responses. Correspondingly, vaccines may be directed against "stealth" epitopes, overriding viral chicanery.
[h=4]KEYWORDS:[/h] T-cell avidity; T-cell epitopes; antigen presentation; influenza A viruses; mass spectrometry
PMID: 25646416 [PubMed - as supplied by publisher]