Elife 9, e52473 (2020)

Germinal center (GC) formation, T follicular helper (TFH) cells and vaccine responses all diminish with age. In eLife, Linterman and colleagues examine vaccine responses in elderly humans and mice to determine whether these impairments can be reversed. Following trivalent influenza vaccination, elderly (65–75 years old) volunteers showed significantly reduced frequencies of circulating TFH cells as compared to their young (18–36 years old) counterparts. Aged mice (~2 years old) also showed greatly reduced numbers of TFH cells and GCs and reduced antibody production as compared to young (~3 months old) mice following vaccination with nominal antigens. Conventional type 2 dendritic cells (cDC2s) are the main antigen presenting cells involved in driving TFH cell differentiation, and they show reduced costimulatory molecules in aged mice; however, the defect is not cell intrinsic but rather a consequence of the aged microenviroment. In part, the impaired cDC2 function is caused by reduced type I interferon (IFN-I) production resulting from fewer plasmacytoid DCs — the key IFN-I-producing cell. Aged mice receiving the Toll-like receptor 7 (TLR7) agonist imiquimod topically at the vaccination site showed rescue of TFH cell numbers; however, this did not require an intact IFN-I receptor to be present on DCs. These findings suggest that weakened vaccination responses in the elderly might be rescuable by TLR7 stimulation.