Membrane Organization and Physical Regulation of Lymphocyte Antigen Receptors: A Biophysicist’s Perspective

Abstract

Receptors at the membrane of immune cells are the central players of innate and adaptative immunity, providing effective defence mechanisms against pathogens or cancer cells. Their function is intimately linked to their position at and within the membrane which provides accessibility, mobility as well as membrane proximal cytoskeleton anchoring, all of these elements playing important roles in the final function and links to cellular actions. Understanding how immune cells integrate the specific signals received at their membrane to take a decision remains an immense challenge and a very active field of fundamental and applied research. Recent progress in imaging and micromanipulation techniques have led to an unprecedented refinement in the description of molecular structures and supramolecular assemblies at the immune cell membrane, and provided a glimpse into their dynamics and regulation by force. Several key elements have been scrutinized such as the roles of geometry (relative sizes of molecules), lateral organisation, motion in the membrane of the receptors, but also physical cues such as forces, mediated by cellular substrates of different rigidities or applied by the cell itself, in conjunction with its partner cell. We review here these recent discoveries associated with a description of the biophysical methods used. While a conclusive picture integrating all of these components is still lacking, mainly due to the implication of diverse and different mechanisms and spatiotemporal scales involved, the amount of quantitative data available opens the way for physical modelling and numerical simulations and new avenues for experimental research.

Quantitative Methodologies to Dissect Immune Cell Mechanobiology

“…In recent years, biophysical parameters, such as molecular diffusion rates, cell material properties and mechanical force generation, have become increasingly recognized as functionally relevant for biology across various length and time scales [3,4]. Although recent advances in spectroscopy and microscopy have enabled a whole set of new biophysical studies, there remains a lack of quantitative methodologies with sufficient sensitivity to determine the wide range of biomechanical parameters relevant to the function of the human immune response at all scales, from single molecules, to cells and tissues [5][6][7].…”

“…Building on the foundations of biomechanics, the emerging field of mechanobiology aims to uncover how intra-and extracellular mechanics are integrated into cell and tissue function and behaviour, elucidating the relationship between biomechanics and physiology [2,18]. The field represents an integral part of ongoing work that seeks to understand how cells integrate and exploit biophysical mechanisms in concert with genetics and biochemical signalling information across scales [5,19,20]. T cells, key mediators of the adaptive immune response, carry out their function in mechanically diverse and dynamic tissue microenvironments, being continuously subjected to mechanical forces generated within their surroundings [3,7].…”

Controlling T cells shape, mechanics and activation by micropatterning

“…Seminal studies [15][16][17] measuring the kinetic parameters of 2D TCR/pMHC interactions (in a membrane environment) radically contradict studies conducted with molecules in solution and demonstrating very rapid association/dissociation cycles of the same TCR for the same pMHC, the affinity of TCR for its natural ligand being of the same order as the one between adhesive molecules such as ICAM1 and LFA1 18 .…”

“…Recently, and driven by technological, biophysical and biological developments, forces that may be at play at the interface of the T cell and APC while the former scans the latter have been proposed to be crucial for T cell recognition and subsequent activation [18][19][20][21] . Experiments at single molecule scale have tested if TCR/pMHC bond rupture forces 22 or lifetimes 23,24 depends on the quality of the peptide and have proposed that this bond could exhibit a behaviour more complex than expected, namely a catch bond behaviour 23 , where, depending on the peptide, the lifetime of the bond can be modulated and even extended for a range of forces compatible with the ones that cell protrusions may exert 25,26 .…”

Special Issue: Membrane and Receptor Dynamics

“…Decision making by immune receptors to select specific signals over others is an active field due to its significance in immune therapy and biotechnological applications. The current review by Limozin and Puech (2019) investigates the role of altering forces in the organization and function of immune receptors. They have compared receptors present at the surface of lymphoid cells, such as B and T lymphocytes and Fc receptors of natural killer (NK) cells and describe how the cell membrane and membrane-cytoskeleton interactions exert a force on these receptors and in turn regulate their function.…”