Cellular and molecular organisation of long-lived immunoregulatory responses within the lung
Lead Research Organisation:
University of Cambridge
Department Name: Pathology
Abstract
T cells defend us against infections and cancer but can drive unwanted inflammation and tissue damage during infection. Regulatory T (Treg) cells are a specialised immune cell type with suppressive function. While most Treg cells are generated early in life, maintenance of these cells throughout life prevents life-threatening autoimmune and allergic inflammation. Maintenance of Treg populations is therefore essential to healthy ageing, and defects underlie inflammatory disorders, including age-associated inflammation, also called inflammageing. Defective maintenance of Treg responses also impairs Treg-targeted biotechnologies, including Treg cell therapy, tolerogenic vaccines and allergen immunotherapy. While much is now known about how Treg cells develop, we lack a fundamental understanding of how Treg responses are maintained. The purpose of this proposal is to establish how Treg responses are maintained under normal conditions, and with age and inflammation.
Some tissues in our body are maintained by stem cells. We have recently found that a critical property of stem cells, called quiescence, is required for long-lived Treg responses. Focussing our analyses on Treg responses wihtin the lung, this research will determine the molecular and cellular properties and functions of quiescent Treg cells using mouse models, examining their relationship with other Treg cells under normal conditions, and with age and inflammation.
Specifically, we aim to:
1. Determine the the molecular properties, cellular relationships and tissue distribution of quiescent Treg cells within Treg responses of the lung under normal conditions, age and inflammation
2. Determine the cellular fate and functions of quiescent and activated Treg cells during lung homeostasis and inflammation using genetic fate-mapping and conditional deletion experiments in mice
3. Determine molecular mechanisms by which quiescence is programmed and maintained within Treg cells using cutting edge molecular, and DNA and RNA sequencing-based approaches
The focus of prior research in the field of Treg biology has been on the highly activated Treg cells which predominate within tissues. By redefining how we think about Treg responses, we will shift focus of research from activated Treg cells to their long-lived progenitors, leading to new understanding and opportunities for biotechnology/drug development. This fundamental bioscience approach is necessary to pave the way for more effective future therapeutic applications of Treg cells for individuals with autoimmune and allergic disorders, and age-associated inflammation.
Some tissues in our body are maintained by stem cells. We have recently found that a critical property of stem cells, called quiescence, is required for long-lived Treg responses. Focussing our analyses on Treg responses wihtin the lung, this research will determine the molecular and cellular properties and functions of quiescent Treg cells using mouse models, examining their relationship with other Treg cells under normal conditions, and with age and inflammation.
Specifically, we aim to:
1. Determine the the molecular properties, cellular relationships and tissue distribution of quiescent Treg cells within Treg responses of the lung under normal conditions, age and inflammation
2. Determine the cellular fate and functions of quiescent and activated Treg cells during lung homeostasis and inflammation using genetic fate-mapping and conditional deletion experiments in mice
3. Determine molecular mechanisms by which quiescence is programmed and maintained within Treg cells using cutting edge molecular, and DNA and RNA sequencing-based approaches
The focus of prior research in the field of Treg biology has been on the highly activated Treg cells which predominate within tissues. By redefining how we think about Treg responses, we will shift focus of research from activated Treg cells to their long-lived progenitors, leading to new understanding and opportunities for biotechnology/drug development. This fundamental bioscience approach is necessary to pave the way for more effective future therapeutic applications of Treg cells for individuals with autoimmune and allergic disorders, and age-associated inflammation.
Technical Summary
Regulatory T (Treg) cells are rare immune cells with powerful immunoregulatory functions, critical to organismal homeostasis. Loss of Treg cells causes lethal inflammation in mice and humans, while their defective function causes autoimmunity and allergy. Treg cells also limit life-threatening immune damage to tissues during infection. A majority of Treg cells develop in early life, but maintenance of Treg cells throughout life is needed to prevent lethal inflammation. While much is now known about how Treg cells develop, very little is known about how Treg responses are maintained in age and inflammation.
Focussing our analyses on Treg responses within the lung, the purpose of this proposal is to determine how Treg responses are maintained under homeostasis and during anti-inflammatory responses. New data generated within our laboratories shows that quiescence, enforced within a subset of Treg cells expressing the transcription factor BACH2, is required for long-term maintenance of Treg responses. We will test the hypothesis that long-lived Treg responses are hierarchically organised, with quiescent Bach2-expressing progenitor cells self-renewing while giving rise to shorter-lived functionally active progeny within the lung.
Our work is organised into three Aims:
1. Determine the molecular profile, clonal relationships and tissue distribution of quiescent Bach2high Treg cells under homeostatic conditions and lung inflammation.
2. Determine the fate and function of quiescent and activated Treg cells during lung homeostasis and inflammation using genetic fate-mapping and conditional deletion experiments
3. Determine molecular mechanisms of Treg quiescence and maintenance
This will provide fundamental new insight into the cellular and molecular organisation of long-lived Treg responses, laying the scientific foundations for a better understanding of age-related tissue inflammation and for effective future therapeutic applications of Treg cells.
Focussing our analyses on Treg responses within the lung, the purpose of this proposal is to determine how Treg responses are maintained under homeostasis and during anti-inflammatory responses. New data generated within our laboratories shows that quiescence, enforced within a subset of Treg cells expressing the transcription factor BACH2, is required for long-term maintenance of Treg responses. We will test the hypothesis that long-lived Treg responses are hierarchically organised, with quiescent Bach2-expressing progenitor cells self-renewing while giving rise to shorter-lived functionally active progeny within the lung.
Our work is organised into three Aims:
1. Determine the molecular profile, clonal relationships and tissue distribution of quiescent Bach2high Treg cells under homeostatic conditions and lung inflammation.
2. Determine the fate and function of quiescent and activated Treg cells during lung homeostasis and inflammation using genetic fate-mapping and conditional deletion experiments
3. Determine molecular mechanisms of Treg quiescence and maintenance
This will provide fundamental new insight into the cellular and molecular organisation of long-lived Treg responses, laying the scientific foundations for a better understanding of age-related tissue inflammation and for effective future therapeutic applications of Treg cells.
