Completed Infection & Immunity Cancer

Decision-making by lymphocytes

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £2.4M
Period Sept 2017 — Sept 2022

In plain English

AI plain-English summary

Sixty years after scientists first proposed that a “trigger mechanism” starts immune responses, no one has yet agreed on how it actually works. This matters because the immune system’s decision-making process—how a lymphocyte decides to attack or stand down—is the core of both immunity and immunotherapy. Without knowing the trigger mechanism, efforts to boost or suppress immune responses remain partly guesswork. The researchers aim to settle a long-standing debate by testing a specific theory called the kinetic-segregation model, which proposes that receptors are triggered when physical contact between cells pushes away phosphatase enzymes that would otherwise block signalling. Using single-molecule fluorescence imaging, they can now watch these molecular interactions in real time at cell-cell interfaces. If the model holds, it would provide a concrete, testable framework for how lymphocytes integrate multiple signals into a decision. This is fundamental science—there is no immediate clinical application. But a clear mechanistic understanding of lymphocyte decision-making would give immunologists a richer theoretical foundation for designing immunotherapies, much as understanding enzyme kinetics transformed drug development. The work may eventually help explain why some immunotherapies succeed while others fail.

View original technical description
It was recognized sixty years ago that a “trigger mechanism” must initiate immune responses. Today, however, not even the broad features of the mechanism are fully agreed, despite its intrinsic scientific interest and the remarkable clinical utility of modulating lymphocyte behaviour. We do know, however, that it encompasses two separate events: receptor triggering per se, and the integration of multiple triggering outputs. Breakthrough developments in fluorescence imaging mean that we can now study molecular behaviour at cell-cell interfaces at single-molecule resolution, in real time. This means that we can directly test whether TCR triggering is explained by a theory relying on the local, physical exclusion of phosphatases from sites of receptor engagement and phosphorylation, called the kinetic-segregation model. We will explore how 'close-contact' formation affects the interplay of local signaling molecules, and test our theory using quantitative models of receptor signaling. We will also study the emergent properties of the types of modular networks known to mediate downstream signaling in T cells and, building on these findings, test a new, simple theory of signal integration. This programme of work will produce a fuller understanding of decision-making by lymphocytes, and a richer framework for thinking about immunotherapy.

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Researchers

Simon Davis (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Decision Making in Immune Cell Activation
Principles of early T-cell activation.
Investigating triggering events in T&B Lymphocytes
Predicting efficient T cell activation with therapeutic applications.
Differential control of T cell co-stimulation by LFA-1, CD2, and CD28

Original classification

Senior Research Fellowship Basic Renewal

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.