Periodic Reporting for period 4 - TWILIGHT (ToWards Immunisations that Last: the Immunology and Gerontology of Helper T cells)
Période du rapport: 2019-12-01 au 2020-05-31
One of the major achievements of the modern era is the extension of the human life-span through improvements in medical care, nutrition, sanitation and access to clean water. The consequent shift towards older populations creates a challenge for society, not least for medical science: how to enable people to age in good health and remain active throughout their lives. Ageing is accompanied by a functional decline of the immune system, resulting in an increased overall susceptibility to infections that are a major cause of morbidity and mortality in older people. Development of strategies to mitigate or overcome these changes remains one of the major challenges of healthy ageing. One of the most successful medical interventions for preventing infectious disease has been vaccination. However, age-related changes in the immune system mean that older individuals often do not generate protective immunity after vaccination. This leads to an increased prevalence of preventable disease in older people, even with good immunisation programmes in place. Therefore, improving vaccine efficacy in older individuals is a key scientific challenge that, if met, would enable all of us to be healthier and more active throughout our lives. Most vaccines provide protection by generating antibodies that block the ability of a pathogen to establish an infection. However, antibody production after vaccination is diminished in older persons. This project aims to understand the age-dependent changes in the immune system that result in poor antibody production after vaccination, with a specific focus on the contribution of the germinal centre T cell subsets, T follicular helper and T follicular regulatory cells.
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).
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).
Improving vaccine efficacy is key to reducing infection-related morbidity in older people. This project worked with both mice and humans to combine the tractability advantages of mice with the physiological relevance of studying humans to ensure that this research programme delivered mechanistic insight into a complex biological problem that is relevant to healthy ageing. This project identified the aged microenvironment as the main contributor to poor germinal centre formation in ageing, which was associated with impaired formation of T follicular helper cells. Importantly, this project established that defective formation of T follicular helper cells and germinal centre response in ageing is not irreversible, providing a proof of concept that it is possible to enhance the immune response to vaccination in older individuals.