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

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101688624 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2470-9468 (Electronic) Linking ISSN: 24709468 NLM ISO Abbreviation: Sci Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science, [2016]-
    • Subject Terms:
      Aging*/immunology ; Germinal Center* ; Toll-Like Receptor 4*; Aged ; Animals ; Cell Adhesion Molecules ; Humans ; Mice ; Stromal Cells ; Vaccination
    • Abstract:
      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.
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    • Grant Information:
      MC_U105178805 United Kingdom MRC_ Medical Research Council; BBS/E/B/000C0407 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MR/V009591/1 United Kingdom MRC_ Medical Research Council; BBS/E/B/000C0408 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 637801 International ERC_ European Research Council; BB/N011740/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council
    • Accession Number:
      0 (Cell Adhesion Molecules)
      0 (TLR4 protein, human)
      0 (Tlr4 protein, mouse)
      0 (Toll-Like Receptor 4)
    • Publication Date:
      Date Created: 20220506 Date Completed: 20220510 Latest Revision: 20230301
    • Publication Date:
      20240105
    • Accession Number:
      PMC7612953
    • Accession Number:
      10.1126/sciimmunol.abk0018
    • Accession Number:
      35522725