Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination

Abstract

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.

Intrinsic defects in lymph node stromal cells underpin poor germinal center responses during aging

“…In order to understand how stromal cells are affected by aging, and how these changes impact on the generation of GC responses to immunization, we subcutaneously immunized adult (8)(9)(10)(11)(12) week old) and aged (>95 week old) Balb/c mice. The ki67 + Bcl6 + B220 + GC B cell response ( Fig 1a) was reduced in both proportion (Fig 1b) and absolute number (Fig 1c) consistent with previous studies 26,27,34 . The reduction in GC size correlated with a reduced FDC network, where CD21/35 + FDCs (Fig 1d) were reduced in proportion ( Fig 1e) and absolute number (Fig 1f).…”

“…In contrast to B cells, T cell responses are impaired in older individuals. Notably, the magnitude of the Tfh cell response is reduced in mice and humans 34,54 , and their ability to support GC formation 30 and B cell selection 33 is impaired by age. T cell age is, however, not the only contributor to impaired GC responsestransfer of young T cells into aged T cell-deficient mice results in a diminished GC response 36 , consistent with a role for the defective stromal cell response underpinning poor GCs in ageing.…”

“…A reduction in the size, quality and output of the GC in older individuals is observed in a number of infection and vaccination settings 26,27,28,29 . This has been linked to T cell-intrinsic mechanisms 30,31,32,33 , and changes in the microenvironment 34,35,36,37,38 . Age reduces the ability of FDCs to capture and retain antigen 27,39,40 , suggesting an impaired functionality in aging that may underpin poor GC formation.…”

A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice

“…Despite ageing occurring on different time scales in mice and people, many of the cellular and molecular changes that occur with ageing are conserved between the species (17), including those in the immune system such as thymic involution and the loss of naïve T cells (18). The response to vaccination is no exception (19,20); after vaccination, both aged mice (>20 months old) and older humans have reduced vaccine-specific antibody formation, an impaired type I interferon response and fewer T follicular helper cells (21)(22)(23)(24). This impaired immune response to vaccination in older mice and humans has been linked with reduced protection against subsequent infection (25)(26)(27)(28).…”

“…This impaired immune response to vaccination in older mice and humans has been linked with reduced protection against subsequent infection (25)(26)(27)(28). Importantly, interventions that enhance immunogenicity of vaccines in aged mice are also effective in humans (21,27,29,30), demonstrating that aged mice are a relevant pre-clinical model for testing the immunogenicity of new vaccine candidates.…”