TLR signalling alters the phenotype and function of lymphoid fibroblasts and impacts vaccination

Abstract

During infection or immunisation, immune cells must converge in the right place at the right time to generate protective immunity; these movements are controlled by lymphoid fibroblasts. These fibroblasts, through the production of a physical scaffold and migratory cues in the form of chemokine gradients, adhesion molecules and survival factors, form the spatial architecture of the lymph node, and support the development of protective and long-lasting immune responses. Previous research from the group I am working in has shown that Toll-Like Receptor (TLR)4 stimulation boosts lymphoid fibroblast responses and improves the germinal centre (GC) response, including in older mice. However, whether TLR4 signalling in lymph nodes fibroblasts affects the lymph node microenvironment to directly promote GC responses remains unknown. In this thesis I established that lymphoid fibroblasts respond to specific direct TLR stimulation in vitro, producing cytokines and chemokines and upregulating cell surface proteins involved in leukocyte ingress, migration, and differentiation in the lymph node. These findings were recapitulated in vivo, where the addition of TLR ligands to Alum-based adjuvant potentiated lymph node fibroblast activation in response to vaccination and provided an early boost to T follicular helper (Tfh) cell differentiation. This TLR4-driven Tfh cell response was accompanied by a larger GC response, more antibody secreting cell (ASC) bone marrow engraftment and improved serum antibody titre. Together these data establish an indirect yet fundamental role for lymphoid fibroblasts in the regulation of T cells responses, by coordinating the development of a Tfh cell-supporting niche that can enhance B cell responses. These data highlight the potential for targeting lymphoid fibroblasts to overcome age-related immune dysfunction and to enhance vaccine responses.