Aging T cell Immunity to Conserved Viral Epitopes

Abstract

Abstract Although seasonal vaccination is widely accessible, its efficacy is inconsistent. Older individuals, in particular, tend to have difficulty mounting adequate immunity to infection. A possible reason for this struggle may be due to high mutagenesis in influenza hemagglutinin (HA), the major component of vaccines. Since older individuals possess diminished immune repertoire diversity compared to younger individuals, large sweeps in the viral proteome can be devastating. Unlike the antibody response, which primarily targets mutagenic surface proteins like HA; however, the T cell response can target more conserved regions of the viral proteome. Vaccines designed to stimulate T cells may thus provide greater protection in older individuals. To better understand the T cell repertoire in relation to the conserved regions of the viral proteome, we have predicted highly conserved viral T cell epitopes from various influenza strains and used our next-generation sequencing based method, TetTCR-seq HD, to pair T cell receptor (TCR) sequence, antigen specificity, transcriptome, and surface protein expression at the single cell level. In addition to novel antigen discovery, our high dimensional data have revealed the presence of immunity toward highly conserved influenza epitopes in older and younger individuals. Additionally, although age appears to decrease TCR repertoire and antigenic diversity, other factors such as immunodominance toward other viral epitopes, such as human cytomegalovirus, interestingly have a greater impact on the influenza-specific repertoire and phenotype. Our data ultimately indicate that healthy individuals harbor a reservoir of influenza-specific T cells that may be targetable by vaccines.