tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2016 Mar 31. pii: 201603106. [Epub ahead of print]
[h=1]Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses.[/h] Valkenburg SA[SUP]1[/SUP], Josephs TM[SUP]2[/SUP], Clemens EB[SUP]1[/SUP], Grant EJ[SUP]1[/SUP], Nguyen TH[SUP]1[/SUP], Wang GC[SUP]3[/SUP], Price DA[SUP]4[/SUP], Miller A[SUP]5[/SUP], Tong SY[SUP]6[/SUP], Thomas PG[SUP]7[/SUP], Doherty PC[SUP]8[/SUP], Rossjohn J[SUP]9[/SUP], Gras S[SUP]10[/SUP], Kedzierska K[SUP]11[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Memory CD8[SUP]+[/SUP]T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M1[SUB]58[/SUB]and the hypervariable HLA-B*3501-NP[SUB]418[/SUB]antigens. The TCRαβs for HLA-B*3501-NP[SUB]418[/SUB] [SUP]+[/SUP]CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP[SUB]418[/SUB]-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19[SUP]+[/SUP]TCRαβ was selected in HLA-A*0201[SUP]+[/SUP]donors responding to M1[SUB]58[/SUB] This public TCR cross-recognized naturally occurring M1[SUB]58[/SUB]variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19[SUP]+[/SUP]TCR specificity for the WT and mutant M1[SUB]58[/SUB]peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201[SUP]+[/SUP]individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M1[SUB]58[/SUB] Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.
[h=4]KEYWORDS:[/h] T-cell receptor; human CD8+ T cells; influenza infection
PMID: 27036003 [PubMed - as supplied by publisher]
[h=1]Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses.[/h] Valkenburg SA[SUP]1[/SUP], Josephs TM[SUP]2[/SUP], Clemens EB[SUP]1[/SUP], Grant EJ[SUP]1[/SUP], Nguyen TH[SUP]1[/SUP], Wang GC[SUP]3[/SUP], Price DA[SUP]4[/SUP], Miller A[SUP]5[/SUP], Tong SY[SUP]6[/SUP], Thomas PG[SUP]7[/SUP], Doherty PC[SUP]8[/SUP], Rossjohn J[SUP]9[/SUP], Gras S[SUP]10[/SUP], Kedzierska K[SUP]11[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Memory CD8[SUP]+[/SUP]T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A*0201-M1[SUB]58[/SUB]and the hypervariable HLA-B*3501-NP[SUB]418[/SUB]antigens. The TCRαβs for HLA-B*3501-NP[SUB]418[/SUB] [SUP]+[/SUP]CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP[SUB]418[/SUB]-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19[SUP]+[/SUP]TCRαβ was selected in HLA-A*0201[SUP]+[/SUP]donors responding to M1[SUB]58[/SUB] This public TCR cross-recognized naturally occurring M1[SUB]58[/SUB]variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19[SUP]+[/SUP]TCR specificity for the WT and mutant M1[SUB]58[/SUB]peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201[SUP]+[/SUP]individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M1[SUB]58[/SUB] Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.
[h=4]KEYWORDS:[/h] T-cell receptor; human CD8+ T cells; influenza infection
PMID: 27036003 [PubMed - as supplied by publisher]