The Questions

Neutrophil Combo

Image of blood showing circulating lymphoblasts (large purple cells), resting lymphocytes (small purple cells) and red blood cells (dark orange cells)

How does regulation of specific genes in immune cells affect their development and function?

The molecular processes which control the development and function of lymphocytes have been extensively studied from the perspective of cell surface receptors and the associated signalling within the cell. The DNA in your genes is converted into messenger RNA (mRNA) which is then translated into proteins inside your cells. The role of some proteins is to bind specifically to RNA, stabilising it and facilitating/allowing conversion to protein.

Many genes and pathways that are needed in the early development of immune cells are also re-used in mature cells as part of the response to infection.

We aim to understand the roles of RNA binding proteins in lymphocyte development and activation throughout life, and we are developing tools for measuring expression of genes in rare populations of immune cells.

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Dentric Combo

Image shows GIMAP5 (green) and nucleus (blue)

How are the numbers of B and T cells maintained?

In a healthy individual it is important that the number of mature T cells and B cells is maintained at a steady level. This process is termed ‘lymphocyte homeostasis’. The generation of new lymphocytes from stem cells in the bone marrow and thymus is balanced by the loss of mature cells from the rest of the body.

Sometimes numbers of lymphocytes can increase dramatically, for example during infections. Once the infection has been successfully defeated by an immune response, lymphocyte numbers return to a normal level.

We are studying a family of signalling molecules called GTPases of the Immunity Associated Protein family (GIMAPs), which may play a part in the maintenance of lymphocyte populations. The importance of maintaining lymphocyte homeostasis is evident from the detrimental impact on the immune system of treatments or infections that disturb it, e.g. chemotherapy, HIV, idiopathic CD4 lymphocytopenia.

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T Cells Combo

Germinal centre in mouse spleen stained for Follicular B cells (orange), cells that are dividing (green), Regulatory T cells (blue) and all T cells (red)

How does vaccination protect us from infection?

When we are infected by pathogens our immune system responds with the coordinated activation of many different cell types, each with their own specific role to clear the pathogen from the body, and generate immunological memory. Within the adaptive immune system helper T cells and B cells specific for the pathogen are recruited to become ‘effector’ cells and a proportion of these cells will go on to become memory cells that are able to respond quickly to future infections

Germinal centres are sites within tissues such as the tonsils, spleen and lymph nodes where B cells proliferate and differentiate during a normal immune response to an infection or immunisation. Because of the central role of the germinal centre in generating immunological memory, a good germinal centre response is critical for a successful response to vaccination.

We are studying how, with advancing age, the size of the germinal centre response and the efficacy of vaccinations diminish. T cells are one of the primary contributors to this decline.

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B-Cells Combo

Mouse spleen, stained to show B cells producing different antibodies (IgM in green/ IgD in red) and T cells (blue) by Fabien Garҫon

What happens inside T cells or B cells when they get activated?

Phosphoinositide-3-kinases (PI3Ks) are a family of enzymes found inside immune cells. These PI3K enzymes generate chemical signals when the cell is activated. Immune cells can express up to eight different forms of PI3K protein. The PI3K enzymes are used by the cells of the immune system to coordinate defences against pathogens. However, activation of one of these forms - PI3Kδ - is one of the first events to happen inside a T cell or B cell when it is first exposed to a foreign antigen.

A mutation in the gene for PI3Kδ increases the enzyme’s activity and causes an inherited immune disorder (called APDS). This disorder is characterised by poor immune responses against bacterial infections in the lung (pneumonia). We are trying to find out why hyperactive PI3Kδ causes immunodeficiency and whether we can use drugs against PI3Kδ to treat these patients.

In the complex environment of cancer, there is also evidence that shutting down PI3Kδ can tip the balance of the immune response in favour of tumour resistance. We are investigating how this happens.

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Macrophage Combo

Fluorescent microscopy image of immune cells (red) in intestinal wall (green) by Marc Veldhoen

How are immune responses controlled in our intestines?

Epithelial barrier sites such as the skin, respiratory and gastrointestinal tract, form a physical interface between our bodies and external environments. These are not static barriers which just keep the outside world separate from the body, but are a meeting point between a diverse mix of immune cells and the ever-changing population of many different micro-organisms.

A specialised subset of white blood cells, the intra-epithelial lymphocytes (IELs), resides just beneath the epithelial barrier of skin and intestines. The IELs are among the first members of the immune system to interact with, and respond to, microbial populations.

AhR, a receptor molecule expressed in IELs, is a crucial component for the maintenance of the IEL populations in skin and gut and plays important roles in maintaining the physical and immunological barriers that contribute to our lifelong health and well-being.

We study the mechanisms that control the maintenance of resident populations of micro-organisms that promote health, and the prevention of undesirable immune responses that may result in chronic infections, allergies, autoimmunity and an increased risk of cancer.

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Macrophage Combo

Lymph node showing helper T cells (Red), killer T cells (Green) and B cells (Blue) by Fabien Garcon

Why is T cell differentiation so important?

T cells regulate immune function by differentiating into highly specialised cell types that either drive or constrain immune reactions. Consequently, T cells play pervasive roles in health and disease. Whereas helper and killer T cells promote clearance of infections and cancer, regulatory T cells suppress their function to limit excessive immune activation.

However, the suppressive function of regulatory T cells can also prevent effective immune responses against chronic infections and cancer. Thus, mechanisms that control T cell differentiation are attractive targets in the development of new therapies for a broad range of disorders.

Transcription factors regulate cell fate-specification and function within the different stages in T cell development. They play key roles in driving cellular identity and bind to regulatory elements within the genome to control its structure and function.

We study the mechanisms by which transcription factors regulate immune function, which has implications in infection and cancer.

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Macrophage Combo

Model of transcription and 3D nuclear organisation showing how ‘V’ and ‘D’ genes are brought together so that they are close enough to recombine

How does our immune system produce so many different antibodies?

To cope with the enormous numbers of foreign antigens encountered during our lifespan, B cells must produce millions of different antibodies. ‘Recombination’ or shuffling of genes to create variations in the binding site of the antibodies is the first step in generating this huge repertoire.

To create antibodies, a particular type of recombination must occur: VDJ recombination, which involves the cutting and pasting together of one variable (V), one diversity (D) and one joining (J) gene to make a new VDJ segment. This VDJ determines the binding specificity of the antibody. Because there are hundreds of different V genes, tens of D genes and several J genes there is the potential to create a huge range of antibodies, which can bind to any pathogen we encounter. Play our antibody assembly game

The V, D and J genes are clustered on one long piece of DNA – so long that the most distant V genes need help to get close enough to the D and J genes to recombine. The DNA is folded and looped in 3 dimensions to bring these distant genes close together. As well as this 3D folding, other factors, such as the proteins bound to the DNA, can determine which genes are chosen for recombination. Some proteins get in the way of recombination, preventing the DNA from being cut, while others act as signals to attract the ‘recombinase’ proteins which carry out recombination. The proteins bound to the DNA are regulated by signals from outside the cell; defects in these signals can prevent some V genes from recombining, meaning that the antibodies produced will be less diverse. Some signalling to B cells can become impaired with age, and this can reduce the antibody repertoire.

Our research aims to understand these processes required to make so many different antibodies, so that we can identify ways to boost the antibody repertoire in people who are less able to fight infection.

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Macrophage Combo

Neutrophils (immune cells which rapidly respond to invasion) phagocytosing or ‘eating’ antibody-coated red blood cells. Image by Karen Anderson & Tamara Chessa

How are neutrophils controlled?

Work focussed on the role of a family of enzymes (PI3Ks) has led to a greater understanding of the signalling mechanisms which allow receptors on neutrophils to control various aspects of neutrophil function.

While neutrophils are key players in the front line of our immune system, responsible primarily for the recognition and destruction of bacterial and fungal pathogens, they are also involved in the signalling pathways that underlie various inflammatory diseases, e.g. Acute Respiratory Distress Syndrome (ARDS) and rheumatoid arthritis.

We are studying how and why a decline in neutrophil migration to sites of infection, and activation of neutrophils at inappropriate locations that damages otherwise healthy cells, contribute to the fact that older people have a reduced ability to fight infection.

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Macrophage Combo

Image showing where Rac is active in a polarised migrating neutrophil. The red and white areas show high Rac activity at the front and the blue and green areas show low Rac activity at the back. (Image by Anna-Karin Johnsson)

How do neutrophils know which way to move?

‘Rac’ is a protein which acts as a molecular-level switch for the normal function of neutrophils. When switched on it regulates neutrophil migration as well as the production of reactive oxygen species (ROS). Depending which side it is switched on, Rac polarises the cell, giving it a front and back. This polarisation allows the cell to migrate in a specified direction. As a result, neutrophils can migrate to the site of an infection, as well as chase and engulf pathogens such as bacteria. Reactive oxygen species can then be released to damage pathogens or used to degrade and breakdown the engulfed bacteria.

We focus our work on the different proteins which activate this switch, known as Rac-GEFs. The dysregulation of these Rac-GEFs, or Rac itself, can result in inflammatory disorders, when too many neutrophils migrate to sites of inflammation and produce too much ROS, or in immune-deficiencies, when neutrophils are unable to migrate to sites of inflammation or produce ROS.

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