RESEARCH
Physics of Human Immunity in Health and Disease
Biomedical sciences have truly transformed the understanding of health and disease in the last decades. However, there is an increasing recognition that physics underpins the physiology of human immunity. Although most function and behaviour of the immune response is adequately explained by biology, chemistry, and omics, many of its features profoundly depend on physical force. Mechanical force plays an important role in the function of immune cells because this force is the only physical force acting across all scales from the organism down to tissues, cells, and molecules.
The Biophysical Immunology (BPI) laboratory aims to understand the biological significance of mechanobiology on the human immune system in health and disease. For this goal we develop advanced technology, microscopy, and analysis approaches.
Mechanical Forces Matters in the Immune System
Mechanical force has repeatedly been highlighted to be involved in the activation of immune cells. However, 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. In contrast, catch bonds are stabilised by an applied moderate mechanical force.
To a large extent, 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. 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.
Research Goal and Objectives
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 aims therefore to identify and dissect the mechanisms of mechanobiology controlling immune cells in health and disease. For this objective of the study of the function and behaviour of immune cells, we develop and apply new technology with the sensitivity demanded by the biology of the immune system.
Research Environment
The BPI Lab led by Prof Marco Fritzsche is located at Rosalind Franklin Institute and the Kennedy Institute for Rheumatology (KIR) at the University of Oxford in the UK. The BPI Lab is strongly engaged in the leadership of the Oxford-ZEISS Centre of Excellence in Biomedical Imaging.