Mechanisms of CD4+ regulatory T (Treg) cell stability in health and disease
Lead Research Organisation:
Babraham Institute
Department Name: Immunology
Abstract
T cells coordinate immune function by differentiating into highly specialised cellular lineages that either promote or suppress immune reactions. Whereas effector T cells drive immune activation and can cause clearance of infections and cancer, regulatory T cells, dependent upon the transcription factor Foxp3, suppress their function to prevent excessive immune reactions. Stability of regulatory T cell populations is required throughout life to maintain immune homeostasis. In cancer, however, regulatory T cells suppress effector responses and their remarkable stability is a barrier to immune-mediated clearance of disease. It is important to understand how stability of regulatory T cells is programmed if new immune-based therapies that manipulate regulatory T cell stability are to be developed for a variety of disorders.
This project aims to determine molecular mechanisms of regulatory T cell stability. We have recently identified a transcription factor protein, BACH2, that functions as a pervasive regulator of immune activation, promoting the formation of regulatory T cells while suppressing the differentiation and function of multiple effector lineages [1]. Genetic polymorphisms within the BACH2 locus are associated with susceptibility to numerous autoimmune and allergic diseases in humans and deletion of BACH2 in mice results in spontaneous lethal inflammation. The function of BACH2 within regulatory T cells is currently unknown. We have found that BACH2 predominantly binds the genome at enhancers and controls expression of distant genes. The proposed project will extend our understanding of the molecular and epigenetic mechanisms by which BACH2 controls the stability of regulatory T cells during homeostasis and in cancer using cutting edge mouse genetics and tumour models. This will identify new targets for development of drugs aimed at manipulating immune function in patients with autoimmunity and cancer.
This project aims to determine molecular mechanisms of regulatory T cell stability. We have recently identified a transcription factor protein, BACH2, that functions as a pervasive regulator of immune activation, promoting the formation of regulatory T cells while suppressing the differentiation and function of multiple effector lineages [1]. Genetic polymorphisms within the BACH2 locus are associated with susceptibility to numerous autoimmune and allergic diseases in humans and deletion of BACH2 in mice results in spontaneous lethal inflammation. The function of BACH2 within regulatory T cells is currently unknown. We have found that BACH2 predominantly binds the genome at enhancers and controls expression of distant genes. The proposed project will extend our understanding of the molecular and epigenetic mechanisms by which BACH2 controls the stability of regulatory T cells during homeostasis and in cancer using cutting edge mouse genetics and tumour models. This will identify new targets for development of drugs aimed at manipulating immune function in patients with autoimmunity and cancer.
People |
ORCID iD |
Rahul Roychoudhuri (Primary Supervisor) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/N503642/1 | 01/10/2015 | 30/09/2019 | |||
1642652 | Studentship | BB/N503642/1 | 01/10/2015 | 30/09/2019 |
Description | Transcriptional and epigenetic programmes of lung inflammation |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | A key commercial collaboration between Rahul Roychoudhuri (RR) and GlaxoSmithKline (GSK)/Epinova, which is now supported by two BBSRC CASE awards, aims to understand the transcriptional and epigenetic programmes that promote lung inflammation. We aim to define transcriptional and epigenetic mechanisms by which airway immune homeostasis is maintained by transcriptional and epigenetic regulators. |
Collaborator Contribution | Support of CASE awards, co-supervision of PhD students, supply of pharmacological agents for use as tool compounds in assessment of epigenetic regulators |
Impact | We have gained an understanding of how lung inflammation is restrained by suppression of ILC2 activation and promotion of Treg differentiation by the transcription factor BACH2 and are exploring mechanisms by which BACH2 may regulate epigenetic programmes in T cells |
Start Year | 2016 |
Description | Babraham Institute Schools Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | A group of six 6th form students were hosted at the laboratory and performed an experiment to resolve the cellular composition of secondary lymphoid tissues using flow cytometry. Students dissected mouse tissues, processed tissues into single cell suspensions, and used fluorescent labelling to distinguish a variety of immune cell populations |
Year(s) Of Engagement Activity | 2017 |
Description | School visit to the Roychoudhuri laboratory for hands-on experience in flow cytometry and cellular immunology |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Two groups of six school children were hosted in the laboratory and were provided hands-on experience processing tissues and using flow cytometry to distinguish populations of lymphoid cells in secondary lymphoid organs using multiparameter flow cytometry. Students were also taught basic scientific background relating to the adaptive immune system |
Year(s) Of Engagement Activity | 2019 |
Description | School visit to the Roychoudhuri laboratory for hands-on experience in flow cytometry and cellular immunology |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Two groups of six school children were hosted in the laboratory and were provided hands-on experience processing tissues and using flow cytometry to distinguish populations of lymphoid cells in secondary lymphoid organs using multiparameter flow cytometry. Students were also taught basic scientific background relating to the adaptive immune system |
Year(s) Of Engagement Activity | 2017 |