Imperial College London
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DrAliceDenton

Faculty of Medicine, Department of Immunology and Inflammation

Senior Lecturer
 
 
 
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Contact

 

a.denton

 
 
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Location

 

9N4bCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Denton:2022:10.1126/sciimmunol.abk0018,
author = {Denton, AE and Dooley, J and Cinti, I and Silva-Cayetano, A and Fra-Bido, S and Innocentin, S and Hill, DL and Carr, EJ and McKenzie, ANJ and Liston, A and Linterman, MA},
doi = {10.1126/sciimmunol.abk0018},
journal = {Science Immunology},
pages = {1--17},
title = {Targeting TLR4 during vaccination boosts MAdCAM-1+ lymphoid stromal cell activation and promotes the aged germinal center response},
url = {http://dx.doi.org/10.1126/sciimmunol.abk0018},
volume = {7},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Denton,AE
AU  - Dooley,J
AU  - Cinti,I
AU  - Silva-Cayetano,A
AU  - Fra-Bido,S
AU  - Innocentin,S
AU  - Hill,DL
AU  - Carr,EJ
AU  - McKenzie,ANJ
AU  - Liston,A
AU  - Linterman,MA
DO  - 10.1126/sciimmunol.abk0018
EP  - 17
PY  - 2022///
SN  - 2470-9468
SP  - 1
TI  - Targeting TLR4 during vaccination boosts MAdCAM-1+ lymphoid stromal cell activation and promotes the aged germinal center response
T2  - Science Immunology
UR  - http://dx.doi.org/10.1126/sciimmunol.abk0018
UR  - https://www.ncbi.nlm.nih.gov/pubmed/35522725
UR  - https://www.science.org/doi/10.1126/sciimmunol.abk0018
UR  - http://hdl.handle.net/10044/1/96743
VL  - 7
ER  -
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