Overview and broad aims
Our research aims to generate a biological understanding of the molecular and cellular events responsible for the decline in the function of the immune system seen with age. By using mouse models and human samples combined with innovative technologies we can uncover the detail of the molecular pathways, cellular interactions and microenvironment effects that together govern an effective immune system.
The combined purpose of our work is to enable the development of approaches, such as vaccines, small molecules and biological/cellular therapeutics, to maximise immune protection and utilise the power of the immune system. In this way, our research aims to support health throughout the life course.
Progress and research highlights in 2023 and 2024
At the heart of the immunological response to vaccination is the germinal centre – hubs of intensive cell communication and coordination in secondary lymphoid tissue. The germinal centre response generates long-lived antibody secreting plasma cells and memory B cells.
With advanced age the formation of germinal centres is delayed, their size reduced and the quality of the antibody response impaired. Work published by the Linterman lab () showed that the spatial organisation of the germinal centre is changed in ageing. Through a combination of mouse research, computer modelling and analysis of human vaccination data, they showed that changes to key interactors of B cells in the light zone of the germinal centre, T follicular helper cells (Tfh), and also to light-zone specific cells – follicular dendritic cells (FDCs) – were at the heart of the diminished vaccination response.
Parallel work () showed that B cell extrinsic factors are also responsible for the poor-quality germinal centre response in ageing, highlighting the significance of the germinal centre microenvironment. These findings implicate the lymph node microenvironment and Tfh cells as targets for vaccine formulations that promote antibody mediated immunity in the later years of life.
We were delighted to expand our expertise in germinal centre biology with the recruitment of Professor Kai-Michael Toellner. Kai’s expertise in immune cell differentiation, antibody production and how long-term immune memory is formed is highly synergistic to the work of the programme with several opportunities for combined approaches.
The germinal centre-focused work is complemented by investigating the molecular pathways that act within T and B cells to regulate the formation, persistence and responses of lymphocytes. Work in the Turner lab continued to investigate the mechanisms, mediated by RNA binding proteins of the ZFP36-family, that govern T cell effector function. They identified a role for ZFP36L1 in sensing antigen affinity and promoting the expansion of high affinity T‐cell clones by regulating sensitivity to cytokine signals ().
The programme welcomed Professor Yiliang Ding as an honorary group leader, building on a research collaboration with the Ribeiro de Almeida lab and opening up the application of Yiliang’s innovative approaches to investigate RNA structure and RNA– protein interactions to the work of several groups across the Ӱԭ.
Our technology-driven approach and growing expertise in proteomics methods has delivered insights into the proteome changes during B cell maturation, advancing what we know about how cell identity and specialisms are established in B cell subsets (). Excitingly, this work suggested that the immune system might prime for rapid action using mRNAs to enable expediated B cell responses.
Impact highlights
In October 2023, Michelle Linterman joined the GSK Immunology Network. Made up of internationally recognised scientists, the programme bolsters connections by embedding academics in GSK laboratories. As a member, Michelle advised on the development of immunology programmes, accelerating the application of our discovery research to support health.
An international partnership between the Ӱԭ and the Malaghan Ӱԭ of Medical Ӱԭ in New Zealand, was supported through a BBSRC International Partnering Award. The partnership unites expertise in the Linterman and Turner labs with the Malaghan Ӱԭ’s novel mRNA vaccine development platform and expertise in full spectrum flow cytometry. Part of the work will be carried out by Theresa Pankhurst, Linterman lab postdoctoral researcher and holder of the inaugural Te Urungi Churchill By-Fellowship from the Malaghan Ӱԭ.
The data collected by Salerno et al. was published as an open-access data resource via the Immunological Proteomic Resource, contributing to this detailed map of the immune cell proteomes as a resource for the research community. The ImmPRes resource integrates data derived from high-resolution mass spectrometry analysis of mouse hematopoietic populations to allow the rapid exploration of the protein landscape of key immune cells.
Looking ahead
A Wellcome Ӱԭy Award is supporting work in the Turner lab to generate approaches to define how the dynamics of protein and RNA interactions affect immunity and immunological memory.
We will also continue to develop our capabilities in human immunology, so that we can translate our findings from mouse models.
In a cross-programme endeavour, we will investigate RNA binding proteins in the context of the regulation of proteotoxic stress using immune cells as models. This has important consequences for the extended lifespans of antibody secreting cells.