Investigating virus-specific t-dependent antibody responses in early life and their modulation by farmyard microbes
File(s)
Author(s)
Labeur Lurman, Lucia
Type
Thesis
Abstract
T follicular helper cell (TFH) dependent antibody responses are critical for long term immunity, but are compromised early in life. Respiratory syncytial virus (RSV), the most common cause of viral bronchiolitis in infancy, promotes limited antibody responses in early life when compared to adults leading to increased susceptibility to reinfection. Using a murine model of RSV, I found that the decrease in neonatal TFH differentiation was associated with differences in key components regulating the signalling of IL-2. These included increased secretion of IL-2 in early life and increased expression of IL-2 receptors on neonatal naïve CD4+ T cells, which were also more prone to phosphorylate STAT5, a TFH antagonist, when compared to adult counterparts. Continuous intranasal exposure of mice to the lyophilised farmyard microbe Acinetobacter lwoffii F78 (A.lwoffii) during recurrent RSV infection was sufficient to bypass the early life IL-2 mediated suppression and augment TFH and RSV-specific antibody responses both systemically and locally, but this was not observed with short-term exposure to the bacteria. Continuous A.lwoffii also boosted conventional dendritic cell type 2 (cDC2) proportions in mediastinal lymph nodes, increased cDC2 expression of CD25 (the secreted form of which can quench IL-2 from the microenvironment) and IL-6, a pro-TFH cytokine. Likewise, in vitro stimulation of bone marrow derived DCs (BMDCs) with A.Iwoffii, but not RSV, potently induced both CD25 and IL-6 secretion. This was partly replicated by LPS but not by TLR3, 7 or 9 agonists. Co-culture of A.Iwoffii-stimulated BMDCs with naïve CD4+ T cells promoted TFH-like differentiation, a process RSV-stimulation of BMDCs inhibited. A.lwoffii exposure also enhanced IL-6 production by B cells both in vivo and in vitro. Together, this data highlights the ability of microbiota to overcome the IL-2-dependent restriction in early life, at least partially, by modulating cDC2s and B cells, and promote antigen-specific antibody mediated immunity.
Version
Open Access
Date Issued
2024-07-29
Date Awarded
2025-04-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Harker, James
Saglani, Sejal
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)