Targeting TLR4 during vaccination boosts MAdCAM-1+ lymphoid stromal cell activation and promotes the aged germinal center response

The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule–1 (MAdCAM-1)–expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1+ stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1+ stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people. Description Targeting TLR4 with GLA-SE boosts lymphoid stromal cell and GC responses to protein immunization in aged mice. MAdCAM-1 about aging As people age, their immune responses to vaccines and infections diminish, increasing the risk for serious illness. These diminished immune responses have been tied to poor germinal center responses in older people, yet the exact mechanism for how this occurs is unclear. Here, Denton et al. vaccinated adult or aged mice with NP-KLH formulations to track germinal center responses overtime. They found that the microenvironment of the lymph node was impaired in older mice, defined by a poor response of MAdCAM-1+ stromal cells to vaccination. These MAdCAM-1+ stromal cells were partially rescued with a TLR4 agonist, which improved the initiation of germinal center immune responses. Together, these data suggest that targeting TLR4 might improve the efficacy of vaccination in older people.