CD4+ T Cells Recognize Conserved Influenza A Epitopes through Shared Patterns of V-Gene Usage and Complementary Biochemical Features

Abstract

Summary T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated by the highly variable T cell receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes by using identical or highly related TCRs expressed on CD8 + T cells. Characterization of these TCRs has extended our understanding of the molecular mechanisms that govern the recognition of peptide-HLA. However, few examples exist for CD4 + T cells. Here, we investigate CD4 + T cell responses to the internal proteins of the influenza A virus that correlate with protective immunity. We identify five internal epitopes that are commonly recognized by CD4 + T cells in five HLA-DR1 + subjects and show conservation across viral strains and zoonotic reservoirs. TCR repertoire analysis demonstrates several shared gene usage biases underpinned by complementary biochemical features evident in a structural comparison. These epitopes are attractive targets for vaccination and other T cell therapies.

HLA‐dependent variation in SARS‐CoV‐2 CD8 + T cell cross‐reactivity with human coronaviruses

“…First, we set out to identify any shared biochemical features of these public TCRs which recognize only SARS‐CoV‐2‐HCoV peptides compared with those which recognize only non‐homologous SARS‐CoV‐2 peptides [ 56 , 59 , 60 , 61 , 62 ]. Between these two groups, we observed only minor differences in CDR3 motifs and lengths of these sequences, for which the effect of technical variation could not be ruled out (Figure S5a–d ).…”

The Many Faces of CD4+ T Cells: Immunological and Structural Characteristics

“…One immunogenic peptide generated from the surface glycoprotein Haemagglutinin (HA), namely HA 306–318 , is able to be presented by multiple HLA-DR alleles [ 62 , 63 ]. Numerous studies have characterised CD4 + T cell responses towards this universal HA 306–318 peptide [ 15 , 64 , 65 ] including their recognition of the pHLA-II complex [ 15 , 16 ]. Two CD4 + TCR structures have been solved in complex with HA 306–318 presented by HLA-II molecules ( Table 1 ) offering insight on how CD4 + TCRs can recognise influenza epitopes.…”

“…Both structures comprise HLA-DR1 presenting the HA 306–318 peptide. The first structure was published in 2000 [ 16 ] and the second structure more recently in 2020 [ 15 ]. The two TCRs (HA1.7 and F11) share the same TRAV, but different TRBV genes ( Table 1 ), and both TCRs bind to HLA-DR1- HA 306–318 in a canonical docking mode, with a similar number of contacts with the pHLA-II.…”

Balanced Cellular and Humoral Immune Responses Targeting Multiple Antigens in Adults Receiving a Quadrivalent Inactivated Influenza Vaccine

“…We further examined pre-existing and vaccine-induced responses to both HA and other influenza viral proteins (NA, M1, M2, NP, NEP, NS1, PA, PB1, and PB2) that may potentially elicit T cell responses [ 12 , 13 ]. Previous studies found that the majority (>80%) of pre-existing CD4 and CD8 T cell responses to influenza A virus strains (H3N2 and H1N1) are directed to the more conserved core proteins (NP/M/NS/PA/PB) and may mediate cross-reactive protection against different influenza A strains [ 39 ].…”

“…Even though extensive studies have reported that both CD4 and CD8 T cells recognize conserved influenza epitopes from viral proteins other than HA [ 12 , 13 ], the study of the cellular immune responses elicited by influenza core protein components in vaccination settings, and particularly in response to Flucelvax immunization are lacking. Hence, studying how non-HA viral proteins contained in Flucelvax contribute to the vaccination response is of interest.…”