How do lymphocyte proliferation and survival contribute to immunological memory in health, ageing and HIV infection?

The immune system protects us from infections by ?remembering? the infections we have encountered in the past to stop them causing harm again. How does the immune system do this? It sets aside families of cells called lymphocytes, each specific for a particular infection. Paradoxically, these cells appear to be short-lived (weeks-months), whereas we know that immune memory lasts years-decades. The immune system must preserve these families of ?memory cells? somehow, but at the same time it must accommodate new families of memory lymphocytes, as new infections are encountered, and also retain sufficient numbers of cells to combat new microbes.

Problems occur when this system of protection fails. Two common situations leading to problems in the immune system are ageing and HIV infection; both affect an increasing proportion of our population. As we age, the immune system becomes less able to combat infections. This results from an imbalance between different families of memory cells. HIV infection damages some immune cells directly, but it also affects all memory cells indirectly, making immune problems worse. We still do not understand how exactly this happens.

This project investigates how long-term immune memory is maintained by measuring the division rate and survival of different families of lymphocytes within the human body. We will assess how many are short-lived, long-lived and very long-lived by applying four different kinds of measurement, three depending on harmless tracers given to track how fast cells divide, and one measuring changing amounts of radioactive carbon naturally found in the body. The project represents a collaboration five different centres: London, Oxford Cardiff, Stockholm and the National Institutes for Health in the USA.

Understanding why the immune system is weaker in the elderly will help us devise ways to prevent this decline and design better vaccination schemes for elderly people. Understanding immune memory in HIV infection will help us think of new ways to help the immune system fight the virus and improve the use of vaccination in people with HIV/AIDS.

Our results will be made widely available to the general public, through the press, and to those specifically interested, eg. those who wish to ensure they stay healthy as they age and those affected by HIV/AIDS, through specialist interest groups and lay publications.

Background
Human T cell memory depends upon maintaining populations of memory lymphocytes cells for many years or decades. When immune memory fails, either gradually, as in immunosensecence (ageing of the immune system), or dramatically, as in HIV/AIDS, the consequences are profound. In both pathologies, lymphocyte populations are characterised by increased proportions of highly-differentiated cells.
Objectives
Memory T cell populations are highly dynamic with short average life-spans. The balance between the need for long-lived memory and the need for continual remodelling is achieved by a systematic balancing of proliferation and death/phenotype transition across the whole T cell pool. How this balance is achieved without compromising long-term memory remains poorly understood and is the focus of this project. The primary aim of this project is to understand in quantitative terms how long-term T cell memory responses are (i) maintained in health, (ii) impaired in ageing, or (iii) lost in HIV infection.
Methods and experimental design
We will use in vivo isotopic tracer methods to measure the turnover of human T-lymphocyte populations. These methods are now well-developed, but different approaches have different biases: in vivo deuterium-labelled glucose-labelling detects proliferation in short-lived cells (and can be further biased to very-short-lived cells by Annexin V+ sorting), whilst heavy water labelling is biased towards longer-lived cells, and 14C enrichment studies measure the survival of only very long-lived cells. We will exploit these differences by combining measurement modalities (together with Ki-67 labelling, which gives complementary information), making multiple measurements in the same subjects. We will then use multi-compartment mathematical modelling to develop models with the best overall fit for the kinetic properties of, and inter-relationships between, different phenotypically-defined subpopulations (CD4/CD8; naive, effector-memory, central-memory and CD45-revertant memory cells). Models will be developed in young healthy subjects (n=8), then applied to elderly subjects (n=8) and subjects with HIV-infection (treatment naive, n=8) to assess the impact of these pathologies on T-cell kinetics. Further sub-studies of CD57+ (?senescent) cells in the elderly and PD-1+ (? short-lived) cells in HIV infection will allow us to address the specific contribution of these cell-types.
Application
The information obtained will help us better understand human immune homeostasis and develop new strategies for optimising immunity in the elderly and novel immune strategies for HIV.