TLR signalling alters the phenotype and function of lymphoid fibroblasts and impacts vaccination
File(s)
Author(s)
Cinti, Isabella
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2024-01
Date Awarded
2024-04
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Denton, Alice
Publisher Department
Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)