Anergic B cells and altered tryptophan metabolism are linked to seasonal influenza vaccine hyporesponsiveness in aged individuals 4276

Description Although older individuals suffer the greatest burden of influenza A virus morbidity and mortality, influenza vaccination effectiveness declines with age. To determine B cells’ role in influenza vaccine hyporesponsiveness, plasma and peripheral blood mononuclear cells (PBMCs) were collected from young (18-40 y.o.) and aged (≥65 y.o.) volunteers before and 7, 14, and 30 days after influenza vaccination. Consistent with past literature, aged individuals exhibited significantly reduced hemagglutination inhibition (HAI) titers and seroconversion toward H3 HA compared to younger donors. Unsupervised clustering of serological data revealed group 1 HA, group 2 HA, or neuraminidase immunodominant responses, as well as generally hyporesponsive individuals. Single cell RNA sequencing of selected donors revealed naïve B cells with an anergic transcriptional program were upregulated in aged individuals. These anergic cells exhibited upregulation of FCRL3, a known inhibitory receptor, and CD96, previously uncharacterized in B cells, which we demonstrated to inhibit B cell receptor calcium signaling and activation. Cellular and plasma metabolomics revealed altered tryptophan metabolism and increased kynurenine levels in aged individuals, and kynurenine was shown to induce anergy and CD96 expression in B cells. These data implicate kynurenine in reduced influenza vaccine effectiveness in aged individuals and suggest this pathway as a promising target to overcome B cell immunosenescence. Funding Sources Supported by NIH U01AI165442 and T32AI007386 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)