PH. Puech
Collaboration: Y. Hamon (CIML), P. Pierobon (Institut Cochin), J. Husson (LaDHyX), D. Gonzalez Rodriguez (U Metz)
Responses of living system to external inputs are surprisingly fast and robust. Such responsiveness has recently been attributed to living systems being poised at criticality, ready to transition from a meta-stable state to another. Although the idea is extremely enticing from the physics point of view, there is a lack of specific biological examples where well-defined observables of criticality have been identified and quantified. Here we propose to study a fundamental biological system that shows critical behavior which is moreover sensitive to mechanical cues, is relevant for cell biology and immunology and is at the core of our immune response: the activation of a T lymphocyte (a crucial type of immune cell) by a so called antigen presenting cell. This system involves communication (chemical and mechanical) between two isolated cells. We hypothesize that both cells are poised at criticality, i.e., near a phase transition, and that their mutual control interlocks them at a self-organised critical point.
Fig: Methodology & tools. A. We propose to measure mechano-biochemical phase diagrams of T and B cells, by imposing different regimes of molecular densities & substrate mechanics, while probing activation, cell shape and mechanics. B. We will benefit from our knowledge of T and B cell biology, and from existing quantitative imaging and force based techniques (eg. traction force microscopy, micropipettes and AFM) already present in our labs. C. We will use molecular probes such as GEMs that we recently adapted to T cells (image : Jurkat) and microfluidic tools to obtain a large body of measurements in space and time, over populations of cells probed at the single cell level, to complement the techniques shown in B.
The goal of this project is to investigate whether the immunological recognition and activation through the establishment of an immune synapse can be described in the framework of self-organized criticality. Our hypotheses are (i) that T-cell activation can be described as a phase transition, (ii) that quiescent T cells operate near the activation critical point, and (iii) that the T/B cell interface regulates the phase transition. To describe T-cell activation as a phase transition, we will conduct experiments of T-cell activation on an inert substrate and construct a phase diagram of activation as a function of substrate parameters, such as antigen concentration and rigidity. We will quantify different activation observables, including chemical responses (such as calcium signalling), morphological changes, and mechanical changes in cellular properties, in order to gain insight into the intracellular mechanics at play. To quantify criticality features, we will conduct large T-cell population studies using a microfluidic platform to parallelize the experiments. We will next perform experiments of T-cell activation in contact to B cells, which we anticipate to have a significant effect on the phase transition.
Our proposed application of the physical framework of criticality to lymphocyte activation is expected to set a new physical paradigm for the immune synapse, with enormous consequences for our understanding of health and disease.
This project is funded by the ANR Criticality (2024-2028, coordinator PH Puech).
Also, tools are developped in the frame of the FR/MEX IRP BioPhysImmuno (Coord. PH Puech).
Adhesion & Inflammation Lab 
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