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Tissue Immunosurveillance by T cells

We investigate how tissue integrity is maintained and restored by T lymphocytes resident within sites such as skin, gut, and reproductive tract. 

Our focus is gamma-delta T cells, discovered following our identification of T cell receptor (TCR) gamma-chain genes. We have shown that the gamma-delta TCR uses a germline (innate) motif to engage butyrophilin-like molecules (of hitherto unknown function) expressed by healthy epithelial cells. Upon cell dysregulation, the TCR switches to adaptive recognition of “stress antigens”.  We are now asking how this unique capacity to bridge innate and adaptive immunity relates to disease, and may be exploited in cancer immunotherapy. 

People

Robin Dart

Postdoctoral Clinical Research Fellow

Josephine Eum

Research Assistant

Adrian  Hayday

Professor of Immunobiology

Khiyam Hussain

Research Associate

Magdalene Joseph

Clinical Research Fellow

Projects

Understanding human V-delta-1 T cells

Human V-delta 1 T cells are a subtype of human gamma-delta T cell that is enriched in tissues such as skin and gut. We have developed unique methods to grow these cells, which fuelled the formation of Gamma Delta Therapeutics and Adaptate Biotherapeutics, both now acquired by Takeda with the goal of delivering the cells as cancer therapeutics for solid tumours. However, we seek to understand these cells much better, gaining fundamental immunological insights, and improving therapeutic approaches. High resolution transcriptomics has provided clues to pathways by which these cells are regulated and that are evidently different from those regulating conventional T cells. Of note, they are strongly cytolytic toward tumour cells. Using CRISPR, functional cancer immunology, and biochemistry, we are now validating these findings, obtaining improved understanding of an unique, clinically applicable subset of human T cells.

Using the T cell receptor (TCR) as an innate receptor

The TCR is a defining component of adaptive immunity, because its immense diversity, resulting from somatic cell TCR gene segment rearrangement, empowers the T cell repertoire with capacity to recognise an almost limitless spectrum of peptide antigens. The consequent clonal expansion of cognate T cells alters the immune compartment pro tem: hence the notion of adaptive immunity. By contrast, innate immunity is driven by the use of germline receptors to engage defined ligands, e.g., microbial glycans. In this case, the response is not a clonal one. We found that remarkably TCR-gamma-delta can use both modalities. It has adaptive reactivity to stress ligands and non-clonal reactivity to butyrophilin-like (BTNL) molecules expressed by healthy epithelial cells. The adaptive response can eradicate infected or tumour cells, while the innate response can promote tissue integrity and homeostasis. We seek to understand how the TCR makes this discrimination and to exploit it clinically.

Gamma Delta T cells and the regulation of Inflammatory Bowel Disease

Tissue-associated T cells are enriched in those expressing gamma-delta T cell receptors (TCRs). This is the case in the human colon, where there is a specific subset expressing TCRs composed of V-gamma 4 and V-delta 1 chains. This subset is uniquely regulated by butyrophilin-like (BTNL) molecules expressed by healthy colonic epithelial cells. This interaction seems important in gut homeostasis, consistent with which we have linked genetic defects in it to increased severity of IBD, in particular Crohn’s disease. We are using clinical materials and model systems to understand this in more detail, in search of new therapies for IBD based on curative tissue regeneration rather than on palliative anti-inflammatories.

Awards

Awards

Our laboratory is supported by the Francis Crick Institute, which receives core funding from CRUK (grant FC001093), Medical Research Council (MRC) grant FC001093, and the Wellcome Trust (grant FC001093); Rosetrees Trust and the John Black Charitable Foundation; King’s Together Seed Fund; National Institute for Health Research (NIHR) Biomedical Research Centre for the Infectious Diseases Biobank; Wellcome Trust grant 106292/Z/14/Z; Wellcome Trust Clinical Research Career Development Fellowship and UK COVID-Immunology-Consortium grant C33499/A20265.

Activities

Our laboratory has been consistently engaged in externally-facing activities, including Pint-of-Science, New Scientist Live, Meet a Scientist, and various exhibitions. Our work is on display at the Outwitting Cancer exhibition, open to the public at the Francis Crick Institute.

People

Robin Dart

Postdoctoral Clinical Research Fellow

Josephine Eum

Research Assistant

Adrian  Hayday

Professor of Immunobiology

Khiyam Hussain

Research Associate

Magdalene Joseph

Clinical Research Fellow

Projects

Understanding human V-delta-1 T cells

Human V-delta 1 T cells are a subtype of human gamma-delta T cell that is enriched in tissues such as skin and gut. We have developed unique methods to grow these cells, which fuelled the formation of Gamma Delta Therapeutics and Adaptate Biotherapeutics, both now acquired by Takeda with the goal of delivering the cells as cancer therapeutics for solid tumours. However, we seek to understand these cells much better, gaining fundamental immunological insights, and improving therapeutic approaches. High resolution transcriptomics has provided clues to pathways by which these cells are regulated and that are evidently different from those regulating conventional T cells. Of note, they are strongly cytolytic toward tumour cells. Using CRISPR, functional cancer immunology, and biochemistry, we are now validating these findings, obtaining improved understanding of an unique, clinically applicable subset of human T cells.

Using the T cell receptor (TCR) as an innate receptor

The TCR is a defining component of adaptive immunity, because its immense diversity, resulting from somatic cell TCR gene segment rearrangement, empowers the T cell repertoire with capacity to recognise an almost limitless spectrum of peptide antigens. The consequent clonal expansion of cognate T cells alters the immune compartment pro tem: hence the notion of adaptive immunity. By contrast, innate immunity is driven by the use of germline receptors to engage defined ligands, e.g., microbial glycans. In this case, the response is not a clonal one. We found that remarkably TCR-gamma-delta can use both modalities. It has adaptive reactivity to stress ligands and non-clonal reactivity to butyrophilin-like (BTNL) molecules expressed by healthy epithelial cells. The adaptive response can eradicate infected or tumour cells, while the innate response can promote tissue integrity and homeostasis. We seek to understand how the TCR makes this discrimination and to exploit it clinically.

Gamma Delta T cells and the regulation of Inflammatory Bowel Disease

Tissue-associated T cells are enriched in those expressing gamma-delta T cell receptors (TCRs). This is the case in the human colon, where there is a specific subset expressing TCRs composed of V-gamma 4 and V-delta 1 chains. This subset is uniquely regulated by butyrophilin-like (BTNL) molecules expressed by healthy colonic epithelial cells. This interaction seems important in gut homeostasis, consistent with which we have linked genetic defects in it to increased severity of IBD, in particular Crohn’s disease. We are using clinical materials and model systems to understand this in more detail, in search of new therapies for IBD based on curative tissue regeneration rather than on palliative anti-inflammatories.

Publications

Awards

Awards

Our laboratory is supported by the Francis Crick Institute, which receives core funding from CRUK (grant FC001093), Medical Research Council (MRC) grant FC001093, and the Wellcome Trust (grant FC001093); Rosetrees Trust and the John Black Charitable Foundation; King’s Together Seed Fund; National Institute for Health Research (NIHR) Biomedical Research Centre for the Infectious Diseases Biobank; Wellcome Trust grant 106292/Z/14/Z; Wellcome Trust Clinical Research Career Development Fellowship and UK COVID-Immunology-Consortium grant C33499/A20265.

Activities

Our laboratory has been consistently engaged in externally-facing activities, including Pint-of-Science, New Scientist Live, Meet a Scientist, and various exhibitions. Our work is on display at the Outwitting Cancer exhibition, open to the public at the Francis Crick Institute.

Our Partners

sapienza university of rome logo

Sapienza University of Rome

Takeda logo

Takeda

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Marengo Therapeutics