Dr John James

Supervisor Details

Contact Details

Warwick Medical School, University of Warwick

Scientific Background

Research Interests

T-cells are an essential blood cell-type in our immune system that can eliminate infections to keep us healthy despite constant exposure to pathogens. T-cells contain an intricate signalling network, which decides whether the cells of our body have become infected. Current methods to investigate this important network invariably also lead to its disruption.

We overcome this problem by developing new molecular tools so that we can investigate the signalling network while keeping it intact. We do this by engineering T-cell stimuli that are light-responsive, giving us precise control over signalling in space and time.

This enables us to directly answer questions about how T-cells can calculate the appropriate functional response, in a way not possible with standard techniques. Our goal is to find parts of the decision-making network that could be fine-tuned by drugs to improve our immune system when T-cell function becomes incapable of maintaining our health.

Scientific Inspiration

Richard Feynman: “What I cannot create, I do not understand.”

Supervision Style

In three words or phrases: Supportive, guiding, responsive.

Provision of Training

As a small group, I invariably take responsibility for your technical training at first, provoding a strong foundation to more independence later. As part of your growth as a scientist during your PhD, I would expect you to independently seek out new avenues for learning, including growing your peer network within the university.

Progression Monitoring and Management

Scientific research is very iterative, relying on a back-and-forth between the person doing the research and those guiding it. I expect regular, in-formal discussions about how work is going so that I can provide insights/input so you can get be as efficient as possible in the lab. As I often still do bench-work myself, this might be done in real time! We organise group meetings every two weeks where each group member presents their work, and we all provide feedback.

Communication

We use a Teams group and individual ‘Chats’ to keep the group up-to-date on lab work. I may message at odd times due to childcare duties, but I never expect replies outside of core working hours. I am always available to discuss any issues that are impacting your ability to fulfil your potential or my/our expectations.

PhD Students can expect scheduled meetings with me:

In a group meeting

At least once per week

In year 1 of PhD study

At least once per fortnight

In year 2 of PhD study

At least once per fortnight

In year 3 of PhD study

At least once per month

The meetings will be face to face and I am usually contactable for an instant response (if required) on every working day.

Working Pattern

The timing of work in my lab is completely flexible, and (other than attending pre-arranged meetings), I expect students to manage their own time.

Notice Period for Feedback

I need at least 1 week’s notice to provide feedback on written work of up to 5000 words.

MIBTP Project Details

Current Projects (2025-26)

Primary supervisor for:

Pre-T Cell receptor signalling dynamics and its role in cellular lineage determination

See the PhD Opportunities section to see if this project is currently open for applications via MIBTP.

Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).

Pre-T Cell receptor signalling dynamics and its role in cellular lineage determination

Secondary Supervisor(s): Professor Stephen Royle

University of Registration: University of Warwick

BBSRC Research Themes: Understanding the Rules of Life (Immunology)

Project Outline

In complex biological systems, checkpoints ensure that critical components are functioning correctly. A great example of this is our immune system, which must integrate signals from multiple cell-types to protect us from invading pathogens. T‑cells are an essential part of our immune response and develop in the thymus organ (as thymocytes) along a well-defined pathway, which includes several essential developmental checkpoints (see figure).

These checkpoints not only ensure correct cell development but also normally prevent cells transforming into a highly proliferative state. However in diseases such as acute lymphoblastic leukaemia (ALL), cancerous B‑ and T‑cells manage to subvert these checkpoint controls and proliferate inappropriately^1,2. Therefore, understanding how these decision points are constructed, and how they could be reinforced therapeutically is essential.

At one such checkpoint during the early double negative (DN) stages of T‑cell development, two lineages diverge; the αβ lineage which express the αβ T‑cell antigen receptor (αβ‑TCR), and the γδ lineage which express the γδ‑TCR³. These receptors differ in the immunoglobulin genes expressed and have non-overlapping roles in our immune system. Factors dictating αβ versus γδ lineage choice are not fully understood, although the ‘strength’ of TCR signalling at the divergence point has been suggested as an important factor³. DN T‑cells express either the pre-TCR, which is the precursor of the mature αβ‑TCR, or the full γδ‑TCR. It is proposed that strong pre-TCR or γδ‑TCR signalling promotes the γδ lineage, with weaker signalling biased to the αβ lineage, although signal ‘strength’ is rarely defined. This signalling also initiates in a ligand-independent manner.

Unlike αβ‑TCR or γδ‑TCR complexes, the pre‑TCR is known to be rapidly removed from the cell surface by endocytosis, and this internalisation is a process we have recently recapitulated in non-immune cells⁴. We hypothesise that pre-TCR signalling emanates from spatially distinct compartments within the cell (e.g. lysosomal compartments) compared to the γδ‑TCR and that this disparity instructs the choice of lineage fate. Testing this hypothesis would be the main focus of the PhD project.

You will create receptors that are targeted to alternate cellular locations to determine whether this directly alters signalling function. You will also make use of artificial engineered receptors that can provide an entirely orthogonal input to the signalling pathway, to directly test whether the role of intracellular signalling in conferring lineage commitment can be completely uncoupled from the structure of the receptor.

How these perturbations affect the localisation of downstream pre-TCR signalling will be observed using fluorescently-tagged intracellular signalling components combined with well-described biochemical assays for cell activation. You will also utilise in vitro derived thymocytes that can be differentiated into physiologically relevant αβ and γδ T‑cells using a bone marrow derived stromal cell line. Key advantages of this system over direct isolation of developing T cells include generation of large cell numbers from low amounts of stem cells and the easy manipulation of T cells throughout their development.

Analyses of pre-TCR signalling localisation have essentially not been performed before, either with TCR-expressing cell lines or in thymocytes and will test whether distinct spatial localisation leads to differential signalling, which would be an exciting and new biological mechanism. You will also start new studies to directly investigate human thymocytes and their signalling mechanisms, which have been barely studied at all, and is critical information to translate the fundamental research into clinically useful information.

References

1. Pölönen et al. Nature 632, (2024).
2. Chen et al. Nature 521, (2015).
3. Ciofani et al. Nat Rev Immunol 10, (2010).
4. Smid et al J Cell Biol 222 (2023).