Impact of Ageing on Humoral Immune Protection from Infection

As individuals age, changes in the immune system often mean that older individuals do not form long-term protection when vaccinated and easily become reinfected upon reencounter with virus and bacteria. This fact was highlighted by the SARS-CoV-2 pandemic, but known to be the case for long. To achieve long-term protection antibodies against the infectious agent need to be continuously produced. In our body only one cell type can produce antibodies. These are terminally differentiated B cells, also called antibody producing cells and plasma cells. As consequence, the long-term survival of plasma cells is critical for antibody production and underlies vaccination success and re-infection control. Plasma cells are produced in secondary lymphoid tissues like spleen and lymph nodes and some find safe harbour in the bone marrow where they survive for months, years, decades. Despite the critical importance of plasma cells, we currently do not know i) how to distinguish plasma cells that live-long from those that do not; ii) whether long-term survival of a plasma cells occurs at generation or following its migration to the bone marrow, or both; iii) which cells and signals in the bone marrow support the survival of plasma cells; iv) how the long-term survival of plasma cells is impacted by ageing. This surprising lack of knowledge is in part due to technical limitations and for that reason most studies so far have been performed in vitro, not translating on many occasions to in vivo. Critically we have lacked a tool permitting the identification and isolation of pure truly long-lived plasma cells. In a breakthrough of my laboratory, we have generated and characterised a genetic tool in the mouse that allowed for the first time specific genetic manipulation, time-stamping and fate mapping of plasma cells in vivo, in the bone marrow. Using this tool we have generated the very profile of genes expressed by truly long-lived PCs residing in the bone marrow and identified among other aspects candidate genes that may allow us to identify these cells. We have set a plan to test these genes and define markers of long-lived plasma cells and will study long-lived plasma cell heterogeneity. Because we now can identify truly long-lived PCs, the understanding of the cells and signals in the bone marrow that support plasma cell survival is in reach. We will map the cells and study the crosstalk between them and plasma cells. We will also study a molecule called IL6 that is found abnormally expressed in aged individuals and is associated with plasma cell pathology. We will test if IL6 expression underlies immune dysregulation in aged individuals and set-up new systems to allow easy study of IL6 in the crosstalk between bone marrow cells and plasma cells. Because the biology of long-lived plasma cells is not understood this project may unleash truly novel therapeutic strategies to enhance protective immunity in aged individuals.

Aged individuals display impaired long-term protective immunity following infection and vaccination, as highlighted by the SARS-CoV-2 pandemic, and known previously. Terminally differentiated B-cells also called antibody-producing cells and plasma cells are critical for long-term protective immunity. Protection from infection is dependent on continuous antibody production and hence on plasma cell survival. However, the intrinsic and extrinsic factors determining plasma cell longevity in vivo are not understood. Ageing alters the biology of plasma cells and of stromal cells in the bone marrow where long-lived plasma cells reside, but the impact of ageing on plasma cell longevity has not been studied. These gaps in knowledge are consequence of significant experimental obstacles i.e., the inability to identify, trace and genetically manipulate long-lived plasma cells in vivo in their so-called bone marrow "survival niche". We generated a tool (Jchain-CreERT2) in the mouse that overcomes these obstacles, and it is ideally suited to investigate the impact of ageing on the biology of plasma cells. We will use this tool to identify and characterise pure long-lived plasma cells in aged mice and surface markers that define these cells. The development of additional genetic systems in combination with Jchain-CreERT2 will allow us to determine whether plasma cell longevity is imprinted at generation, after residence in the bone marrow, or both; and we will also use single cell RNA sequencing to enquire long-lived plasma cell heterogeneity. Because we can identify long-live plasma cells we will map bone marrow cell niches and assess the crosstalk between bone marrow niche cells and plasma cells. Finally we will assess functionally how age associated changes in impact plasma cells and bone marrow niches. The insights gathered in this project will help determine feasibility of interventions to enhance protective immunity in aged individuals.