CD169+ subcapsular sinus macrophages are necessary for adjuvant activity of TLR ligands and antigen deposition onto follicular dendritic cells

Abstract

Vaccines are credited with saving millions of lives, yet there still remain infectious diseases with no effective vaccine. Subunit vaccines contain specific components from pathogens, which, cannot stimulate the immune system alone, necessitating the inclusion of an immunostimualtory adjuvant. Toll-like receptor (TLR) ligands, due to their immunostimualliting ability are being explored as potential adjuvants. To further advance vaccine development, thorough investigations need to be performed to characterize cellular interactions within the immune system after stimulation and how adjuvants affect this process including antigen distribution within the draining lymph node. Our studies have focused on a TLR2/TLR1-ligand based adjuvant, PorB, the major outer membrane protein from Neisseria meningitidis. We hypothesized that TLR adjuvants would increase antigen deposition onto follicular dendritic cells (FDC) which would enhance high affinity antibody production and that depletion or knockouts of subcapsular sinus CD169+ macrophages would negatively affect antibody production. We demonstrated that PorB increased FDC frequency and antigen deposition on these FDCs. Further studies examined the role of CD169+ macrophages in PorB adjuvanticity using low-dose clodronate treated mice (which preferentially removes CD169+ macrophages), or CD169 knockout mice. Compared to wildtype controls, low-dose clodronate mice and CD169 knockout mice had greatly decreased antibody response with the use or PorB as an adjuvant along with decreased antigen deposition on FDCs. Together, these data emphasize the effect of adjuvant stimulation on cellular interactions antigen distribution in lymph nodes along with the unique ability of PorB to affect this process.