Molecular basis for universal HLA-A*0201–restricted CD8 ⁺ T-cell immunity against influenza viruses

Abstract

Memory CD8+ 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 58 and the hypervariable HLA-B*3501-NP 418 antigens. The TCRαβs for HLA-B*3501-NP 418 + CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP 418 -specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A*0201+ donors responding to M1 58 . This public TCR cross-recognized naturally occurring M1 58 variants complexed with HLA-A*0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19 + TCR specificity for the WT and mutant M1 58 peptides, suggesting the possibility of universal CTL immunity in HLA-A*0201 + individuals. Combined with the high population frequency of HLA-A*0201, these data potentially explain the relative conservation of M1 58 . 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.influenza infection | human CD8 + T cells | T-cell receptor

CD8+ T cells specific for the islet autoantigen IGRP are restricted in their T cell receptor chain usage

“…S1a). From the analysed cells, we identified new as well as previously described22232930 Flu MP 58-66 -specific T cell receptor chains (see Supplementary Table S1). We noted inter-individual sharing of TCR α-chains among the analysed Flu-specific cells (Supplementary Fig.…”

Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles

“…Assessment of cell division revealed that all memory CD8 + T cell subsets were capable of undergoing in vitro expansion with, on average, 60%-70% of cells within each subset undergoing at least 1 division after 10 days of culture ( Figure 3, B and C). A comparison of the effector function of the divided cells following a brief restimulation revealed that, across all the subsets, 70%-85% of the divided cells could generate IFN-γ and 80%-90% could synthesize TNF-α, reflecting that the progeny of each of the memory CD8 + T cells subsets had supe- (5,16). As predicted, CD8 + T cells directed at distinct epitopes displayed different biases in TCR-β variable (TRBV) and TCR-α variable (TRAV) usage as well as different lengths of complementarity-determining region 3α (CDR3α) and CDR3β loops ( Figure 5).…”

Alloimmune T cells in transplantation

“…EBV-and herpes simplex virus-specific clones have been shown to also react to allogeneic HLA in humans, particularly within the CD8 compartment (21,(61)(62)(63)(64)(65); it has even been suggested that nearly half of the TCRs specific to a given virus may also have alloreactivity (66). Furthermore, these viral peptide-specific TCRs may have "public" sequences shared between individuals with the same presenting HLA allele (67)(68)(69)(70). Notably, cytokine production and other measures of T cell function are not always identical in response to viral antigen and cross-reactive HLA alloantigens (21), perhaps because of differing TCR affinities for different ligands.…”