TransCoMigr

Collective motility, defined as the coordination of individuals to operate displacements as groups, has been reported at all scales of living organisms, from bacteria colonies to human crowds. Despite the diversity of mechanisms regulating collective motility in different biological species, fundamental rules appear to be shared. We propose here to conduct an interdisciplinary project, in which we will explore the principles and mechanisms of collective motility in lymphocytes (partner 1), by merging expertise from well-established models of collective motility: schools of fish (partner 2) and border cells of the fly ovary (partner 3). Lymphocytes are usually described to patrol the organism as fully independent cells. However, our yet unpublished data demonstrate that transformed B lymphocytes can migrate in vitro as collective entities in chemokine gradients, thereby increasing their chemotactic sensitivity. Given the histological evidence of dense lymphocyte cohorts in situ, for example in inflammatory foci, we postulate that lymphocytes can coordinate their migration during tissue infiltration. To first unravel the principles of collective motility in lymphocytes, we will build a computational model based on the expertise acquired by partner 2 on different models including fish schools, insect swarms and human crowds. Astonishing analogies appear to be shared between lymphocyte cohorts migrating in vitro and fish schools, for example regarding the rhythmic succession of distinct phases of coordination. This study is expected to define the key rules, the interactions among lymphocytes and the parameters setting the pulse to the coordinated motility of lymphocytes. To then investigate the molecular mechanisms enabling lymphocytes to migrate as collective entities, we plan to transfer knowledge and tools developed by partner 3 during the study of border cell migration in the Drosophila ovary. We will combine the use of biosensors to induce and monitor the activation of Rho GTPases in lymphocyte cohorts since these molecules act as master switches in the control of cell polarity and actin cytoskeleton remodeling. By analogy to the border cell model, we expect to find specific patterns of Rho GTPase activation during lymphocyte collective chemotaxis. To further explore, downstream of Rho GTPases, how actin cytoskeleton dynamics regulate lymphocyte and border cell collective motility, we will conduct a parallel screen aiming at identifying actin regulators playing a conserved role in collective motility. Beyond our shared scientific interest in elucidating the motility rules of lymphocyte cohorts as a new model of collective motion and in unraveling the molecular control behind it, we are eager to assess the relevance to physiopathology of the coordinated motion of lymphocyte cohort. Based on the expertise of partner 1 in the study of lymphocytes motility and activation in the context of disease, we will first investigate in vitro which maturation stages and environmental settings condition the onset of collective motility in different subsets of T and B lymphocytes purified from human blood. We will then determine which level of coordination is associated to the motility of T lymphocyte cohorts in a murine model of atopic dermatitis characterized by dense skin infiltrates. The originality of this proposal stems from the unexpected observation that lymphocytes can migrate as collective entities in response to chemokines. The mechanisms underlying this phenomenon will be tackled in a truly interdisciplinary manner by bringing together experts of motility from usually separate fields of biology (quantitative ethology, morphogenesis, immunology). Furthermore, it associates an original set of approaches (computational modeling, high-resolution time-lapse microscopy, biosensors, genetic screening) expected to unravel the principles and mechanisms of collective motility in lymphocytes, as well as its relevance to physiopathology.