This project aimed to unravel the cellular and molecular mechanisms that underpin the poor response to vaccination in older individuals. Specifically to understand the age-dependent cellular and molecular changes in the germinal centre T cells, T follicular helper and T follicular regulatory cells, and to determine whether alterations in the microenvironment that are responsible for the impaired germinal centre response following vaccination of older individuals.
Research track 1 focussed on the age-dependent cellular and molecular changes in T follicular helper cells following vaccination:
We have shown that both aged mice and older humans have reduced formation of T follicular helper cells following vaccination and in response to the commensal microbiome in the gut. Importantly, we showed that this defect can be corrected in aged mice, demonstrating that this is not an irreversible feature of the ageing immune system (Stebegg et al., Nat Comms, 2019 and Stebegg, Bignon et al., eLIFE, 2020). This project also established that it is possible to boost T follicular helper cells following vaccination in younger adults using one of the next generation of vaccine adjuvants (Hill, Pierson et al., J Exp Med, 2019). Further we have identified that T cell intrinsic factors can cause altered T follicular helper cell formation in ageing, that is caused by inappropriate activation of the Notch pathway (Webb et al., manuscript in revision).
Research track 2 will investigated the function of T follicular regulatory cells in germinal centre response, in both young and old individuals.
Our data established that excessive formation of T follicular regulatory cells are not causal in the poor germinal centre response in ageing. This research track also delivered new insights into the basic biology of T follicular regulatory cells, identifying that they can be specific for the immunising antigen (Aloulou et al., Nature Communications 2016) and that they do not require CXCR5 expression to access the germinal centre (Vanderleyden et al., Cell Reports, 2020).
Research track 3 investigated the contribution of the aged microenvironment to poor vaccine responses in older individuals.
Here we used adoptive transfers and heterochronic parabiosis to establish that early defects in germinal centre formation are caused by the aged microenvironment that accumulates senescent non-lymphoid cells, and are associated with a defective response in lymph node stromal cells (Denton et al., BioRxiv 2020).
