Title: Heterogeneity of Plasma Cells and of its Survival Niche in the context of Ageing
Funder: Dunhill Medical Trust

Abstract: As individuals age, changes in the immune system often mean that older individuals lack long-term protective immunity following infection or vaccination, as recently shown for SARS-CoV-2. This problem is undoubtedly multifactorial and complex. In this proposal we will focus primarily on the study of plasma cells, also known as antibody-producing cells. Plasma cells are formed during the course of an immune response and the antibody produced by these cells is essential for long-term protection from infection. However, current knowledge does not provide longitudinal information on the impact of age in the biology of plasma cells nor on the cellular composition and properties of plasma cell survival niches required for plasma cells to live long. Our laboratory generated and characterised a genetically engineered mouse model (Jchain-CreERT2), in which a GFP tagged tamoxifen-inducible Cre is expressed under the endogenous locus control of Jchain. This model allows for the first-time specific genetic manipulation and fate mapping of PCs in vivo, in their niche. To generate a fate mapping reporter we crossed the Jchain-CreERT2 mice with a R26 Cre/loxP reporter allele expressing RFP (R26RFP). After immunisation we performed temporally-defined Cre activation through tamoxifen administration allowing the tracing of time-stamped (GFP+RFP+) BM PCs over-time. We analysed BM PCs from adult mice (3-4 months of age) at multiple time-points after time-stamping for a period of 9 months using flow-cytometry and bulk RNA sequencing. Most time-stamped PCs perished within the period of analysis; however a small fraction ~5% survived for at least 9 months. Analysis of the gene expression of FACS purified GFP+RFP+ PCs over-time by bulk RNA-seq revealed that as the time-stamped PC pool became enriched for long-lived cells clear and significant changes in the gene expression profile were detected. However, this dataset lacks single cell resolution required to interpret the underlying biology of the observed change in gene expression profile over-time i.e., it remains to be determined if it is due to the enrichment of imprinted long-lived cells within time-stamped PCs; or instead post-ordination following access and residence in the survival niche; or potentially a mix of both. We thus propose to perform single BM plasma cell RNA-sequencing and antibody sequencing coupled with tissue spatial transcriptomics to investigate longitudinally plasma cell heterogeneity and survival niche composition in adult (3-4 months) and older (>20 months) mice. The overall expectation is to gather age related biological data on long-lived plasma cells and survival niches for the design of larger studies, which culminate in interventions offering enhanced protective immunity to older people.

Lay abstract: As individuals age, changes in the immune system often mean that older individuals lack long-term protective immunity following infection or vaccination, as recently shown for COVID-19. This problem is undoubtedly multifactorial and complex. In this proposal we will focus primarily on the study of plasma cells, also known as antibody-producing cells. Plasma cells are formed during the course of an immune response and the antibody produced by these cells is essential for long-term protection from infection. However, current knowledge does not provide in-depth longitudinal information on the impact of age in the plasma cell population nor on the cellular composition and properties of other cells that interact with plasma cells and that contribute for their survival. Our laboratory generated a new system in the mouse that allows to specifically trace plasma cells over-time after an immune response. We will use this model to investigate the impact age has on both plasma cells and cells that support plasma cell survival. The overall expectation is to gather age related biological data on plasma cell survival and devise ways of intervention that offer enhanced longer-term protective immunity to older individuals.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE