Analysis of mechanisms responsible for maintenance, activation and tolerance of CD4 T cells

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

We are studying factors and mechanisms involved in maintaining a balanced immune system to find out the underlying reasons for autoimmune disease as well as parameters important to induce and maintain immunological memory.

Technical Summary

The aims of this project are: i) To investigate factors involved in survival of naive T cells ii) To study mechanisms and antigen presentation requirements which lead to induction of immunological tolerance and memory formation iii) to study homeostatic control mechanisms in naive and memory T cell compartments iv) To study processes which lead to activation of autoimmune T cells and investigate their regulation Our objectives are to understand how key immunological functions such as tolerance to self versus immunity to foreign antigens are induced and maintained, how immunological memory is generated and preserved and what mechanisms are involved in dysregulation of the immune system leading to autoimmunity or immune pathology. We are closely collaborating with other groups in the Infection and Immunity Group to extend our findings to possible applications in immunity to infectious diseases. Methodology: Novel autoimmune models are generated and parameters involved in causing autoimmunity are investigated. These studies use methods such as quantitative PcR, cloning, transfection, FACS, adoptive cell transfers, immune histology and in vivo and in vitro assays for determination of lymphocyte function. We are generating reporter mice to follow T cell differentiation and survival during immune responses. Summary: i) We showed that survival of naove T cells is differentially regulated in CD4 and CD8 T cell populations ii) we identified the molecular mechanisms underlying differentiation of Th17 T cells which are the main mediators of autoimmune pathology in arthritis and multiple sclerosis. iii) We demonstrated that Th17 T cells depend on interaction between pro-and anti-inflammatory cytokines which determine autoimmune effector function in an animal model of multiple sclerosis iv) We are investigating the involvement environmental toxins in the induction of autoimmunity or immune pathology Implications for improving health or health care and/or increasing wealth: This research investigates basic mechanisms in animal models and there is no direct application in the medium term. However, our studies on Th17 T cells in autoimmunity may lead to novel intervention strategies in autoimmune diseases.

Publications

10 25 50
 
Description Quinquennial Review
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Title RNAseq datasets 
Description We have generated RNAseq data from intestinal haematopoetic cells (dendritic cells, eosinophils, Th17 cells) and organoid cultures from colon 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact We have generated several datasets for transcriptomes that are still in the process of analysis 
 
Title IL-17a Cre mouse 
Description Generation of an IL-17 fate reporter mouse that allows detection of cells that have activated the IL-17 pathway by expression of a fluorochrome independent of whether or not the cytokine is still secreted 
IP Reference  
Protection Protection not required
Year Protection Granted 2014
Licensed Yes
Impact licencing to Medimmune