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

Lead Research Organisation: St George's University of London
Department Name: Clinical Developmental Sciences

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description Biomedical Catalyst: DPFS/DCS Full PROPOSAL
Amount £3,635,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2016 
End 11/2021
 
Description LLR Project Grant
Amount £50,180 (GBP)
Funding ID 12064 
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2012 
End 12/2015
 
Description LLR project grant
Amount £66,918 (GBP)
Funding ID 12024 
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2012 
End 04/2015
 
Title Analysis of LC kinetics by chemokine analysis 
Description As a result of this research we have developed new approaches to analysis of lymphocyte kinetics according to chemokine receptor expression. New cell sorting protocls were developed and new approaches to modelling of quantitative data were employed. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2013 
Provided To Others? Yes  
Impact Still to be published and disseminated 
 
Title Model of LC kinetics in HIV 
Description As a result of this research we have developed novel models for understanding how CD4+ T cells interact with HIV to cause CD4 cell depletion. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? Yes  
Impact To be published and disseminated 
 
Title Models of Lymphocyte kinetics 
Description With Dr Becca Asquith at Imperial College, we have developed approaches to analysis of lymphocyte labelling kinetics. A publication manuscript has been submitted and is under review. 
Type Of Material Data analysis technique 
Year Produced 2014 
Provided To Others? Yes  
Impact Better understanding of labelling kinetics 
 
Description Collaboration on Lymphocyte kinetics in HIV 
Organisation Royal Free Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Clinical studies of turnover of CD4 T cells in HIV
Collaborator Contribution Collaboration in data analysis and interpretationCollaboration in data analysis, interpretation and presentationcollaboration on analysis of HIV viral tropismsCollaboration on mathematical modelling of lymphocyte kinetics
Impact Abstract presentation at CROI 2011
Start Year 2006
 
Description Collaboration on Lymphocyte kinetics in HIV 
Organisation St Mary's Hospital, London
Country United Kingdom 
Sector Hospitals 
PI Contribution Clinical studies of turnover of CD4 T cells in HIV
Collaborator Contribution Collaboration in data analysis and interpretationCollaboration in data analysis, interpretation and presentationcollaboration on analysis of HIV viral tropismsCollaboration on mathematical modelling of lymphocyte kinetics
Impact Abstract presentation at CROI 2011
Start Year 2006
 
Description Collaboration on Lymphocyte kinetics in HIV 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Clinical studies of turnover of CD4 T cells in HIV
Collaborator Contribution Collaboration in data analysis and interpretationCollaboration in data analysis, interpretation and presentationcollaboration on analysis of HIV viral tropismsCollaboration on mathematical modelling of lymphocyte kinetics
Impact Abstract presentation at CROI 2011
Start Year 2006
 
Description Collaboration on Lymphocyte kinetics in HIV 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Clinical studies of turnover of CD4 T cells in HIV
Collaborator Contribution Collaboration in data analysis and interpretationCollaboration in data analysis, interpretation and presentationcollaboration on analysis of HIV viral tropismsCollaboration on mathematical modelling of lymphocyte kinetics
Impact Abstract presentation at CROI 2011
Start Year 2006
 
Description Collaboration with KCH London on CLL 
Organisation King's College London
Department Research Section of Molecular Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of a new project to evaluate the effect of T cell inhibition on in vivo CLL Leukaemic cell turnover
Collaborator Contribution Development of a new project to evaluate the effect of T cell inhibition on in vivo CLL Leukaemic cell turnover
Impact Award of two grants from Leukaemia Lymphoma Research
Start Year 2010
 
Description NIH 
Organisation National Institutes of Health (NIH)
Department Vaccine Research Center (VRC)
Country United States 
Sector Public 
PI Contribution New collaboration with Dr R Koup's group at the Vaccine Research Center, at NIH Bethesda was developed in 2009. this builds on work dones as part of this MRC project.
Collaborator Contribution Development of new concepts and new projects. Learning new techniques and skills.
Impact New proposal currently being drafted
Start Year 2009
 
Description University of Birmingham - Dr Janet Lord 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Developing new investigations and grant application on granulocyte kinetics
Collaborator Contribution Expertise in immune effects of ageing
Impact Grant application to MRC
Start Year 2013
 
Description Use of Tregulatory cells for treatment of IBD 
Organisation King's College London
Department MRC Centre for Transplantation
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of stable isotopes to track Treg in vivo in clinical studies
Collaborator Contribution They lead on the project
Impact None to date
Start Year 2015
 
Description Lunch Club talk for elderly 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact about 50 mostly elderly people attended a talk on ageing and the immune system
"Lunch Plus" hosted by New Malden Baptist church, Surrey - 21/5/2012

Approached by several elderly people willing to participate in research
Year(s) Of Engagement Activity 2012