Research

Physics of Human Immunity in Health and Disease

Biomedical sciences have fundamentally transformed the understanding of health and disease in the last decades. However, there is growing recognition that physics ultimately underpins the physiology of human immunity.

Although most function and behaviour of the immune response can adequately be explained by biology, chemistry, and omics, many of its features profoundly depend on physics. Especially, mechanics plays a pivotal role in the function of immune cells because mechanical force is the only physical force acting across all physiological scales from the human organism down to organs, tissues, cells, and molecules.

The Biophysical Immunology Laboratory seeks to decipher the fundamental role of mechanobiology in the human immune system across health and disease. This involves the relationships of spatial, temporal, force scales for the immune cell function. To achieve this, we pioneer advanced biophysical technologies, optical microscopy, and quantitative analysis approaches.

Image Credit: Shuyang Xu

Research Goal

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Mechanical Forces in the Immune System

Research Goal and Objectives

Research Environment

Measuring single ligand-receptor bonds in real-time to understand the role of mechanical force in immune cell function.

Primary research goal is therefore the understanding of the physics of the immune system across scales from tissues down to cells and molecules.

The BPI Lab is located at Rosalind Franklin Institute and the Kennedy Institute at the University of Oxford in the United Kingdom.

Close-up of an optical tweezers setup with a microscopic bead trapped by a red laser path, measuring piconewton forces, clean laboratory environment

Physics principles of organization of the cellular immune system

T lymphocytes can exhibit emergent collective behaviour governed by the physical principles of self organization rather than passive self assembly. While self assembly relies on the direct exchange of information and molecular cues such as cytokines and direct cell-cell signaling to form static or equilibrium structures, self organization in T cells is an active, far from equilibrium process sustained by cellular energy consumption.

When infiltrating tissues to locate cancer cells, T cells cannot only operate merely as isolated agents. Instead, through hydrodynamic coupling, mechanical interaction, and/or biochemical cues, including chemokines and cytokines, large T cell ensembles whether composed of diverse T cell subsets or uniform populations dynamically coordinate their migration, share environmental sensing, and execute population level decision making. This active organization enables T cell cohorts to optimize spatiotemporal search strategies, mechanically remodel dense extracellular matrices, and cooperatively fight tumours in ways that T cells operating individually cannot achieve alone.

Nevertheless, quantifying the decision making dynamics of large T cell ensembles presents formidable technical hurdles. Standard high resolution microscopy forces a difficult compromise: zooming into individual immune cell target cell interaction obscures the broader ensemble context, while expanding the imaging field of view typically sacrifices the cellular detail required to measure cell cell interaction. Moreover, imaging large populations of interacting cells deep within thick, scattering tissue environments introduces severe phototoxicity and light scattering. Overcoming these experimental bottlenecks relies on advanced optical microscopy such as ultrathin super extended lightsheet microscopy and lattice lightsheet imaging which provide the necessary speed, large field of view, and optical sectioning to visualize how collective T cell ensembles make decisions in health and disease at scale.

Image Credit: Anna Schepers

Mechanical Forces Matters in the Immune System

Mechanical force has repeatedly been highlighted as a critical determinant of function of the human immune system. Nevertheless, the biological significance of mechanical force for example for T cells remains under active consideration.

Over the last couple of years, mechanical force has become known to be involved in all stages of T cell activation. Already at first contact between a T cell and an antigen presenting cell (APC), when T cell protrusions like ruffles and microvilli initiate T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs) on the APC, mechanical forces affect their interaction. Upon engagement of a single TCR–pMHC bond, TCR phosphorylation occurs through recruitment of kinases within a few seconds. The number of total TCR phosphorylation events is thought to determine whether to activate a T cell or not, both, in vitro and in vivo.

The uncertainty about the importance of mechanical force for antigen recognition might in part be due to the fact that the mechanical forces acting on TCR–pMHC bonds are diverse. For example, T cell microvilli during early T cell activation and invadosomes during full T cell activation generate a combination of constant and fluctuating mechanical forces in the pico-newton (pN) range. Furthermore, mechanical forces can have different effects on bond lifetime: slip bonds break faster upon application of a mechanical force, whereas catch bonds are stabilised by an applied moderate mechanical force. Beyond these external forces, we recently described that the intrinsic mechanical properties of the TCR molecules themselves, such as the structural compliance of the TCR, matter profoundly for the activation of T cells (Fritzsche and Kruse, PNAS 2024). Crucially, we discovered a mechanical optimum for the activation of T cells (Fritzsche and Kruse, Trends Open 2026), revealing that T cell triggering relies on a finely tuned physical window rather than arbitrary force magnitude.

This existence of a mechanical optimum has profound implications for human immunity and may explain why cancer cells adopt altered mechanical phenotypes, exhibiting either abnormally soft or hard characteristics to evade immune surveillance. By modulating their physical stiffness, tumor cells can disrupt the precise mechanical engagement required for optimal TCR triggering, throwing off the force optimum and impairing effective antitumor immunity.

Experiments on the role of force in TCR-pMHC binding are so far not quantitatively comparable among each other, chiefly owing to differences in measurement techniques and their sensitivity, a challenge our BPI team with Huw Colin-York and Marcel Issler from the BPI lab have addressed when evaluating cellular force generation and traction force microscopy frameworks (Issler et al, Mechanobiology, 2026; Li & Colin-York et al, Nature Communications 2021; Barbieri& Colin-York et al, Nature Communications 2021; Colin-York et al, Nano Letters 2016 and Nano Letters 2017). For these reasons, differences in the outcomes of the experiments must be interpreted with care. They might be resolved with improved experimental techniques. Yet, such differences might also turn out to be real. A common theoretical and experimental framework for T cell activation remains still elusive, but bridging these mechanical insights will be vital for next-generation immunotherapies.

Image Credit: Marco Fritzsche

Mechano-energetics of the Immune System

Mechanical force generation by T cells depends on their cellular energetics. Navigating complex tissue micro-environments, mounting inflammatory responses, and sustaining antitumor immunity impose massive metabolic demands on T cells. As T cells transition from surveillance within fluid blood vessels to migration and immune synapse formation inside dense extracellular matrices, they must carefully allocate their available energy resources.

When T cells experience the physical constraints of dense tumor matrices or crowded interstitial spaces, energy that would otherwise drive immunological synapse formation and target cell destruction is redirected toward mechanical adaptation and matrix deformation. This energetic trade-off between environmental navigation and cytotoxic activation can lead to insufficient triggering, premature synapse termination, and ultimately T cell exhaustion. Uncovering how T cells balance ATP-derived energy allocation between mechanical tissue interactions and synaptic killing provides a crucial framework for understanding why dense tumors successfully evade immune surveillance and points toward new ways to optimize immunotherapeutic efficacy.

Recent advances from the BPI team utilizing advanced fluorescence lifetime imaging microscopy (FLIM) together with PicoQuant technology allow us to measure the metabolic and energetic states of T cells and the surrounding tissues in health and disease (Purdie et al., Nature Communications Medicine 2026).