Gérard Group | Spatiotemporal Dynamics of T Cell Responses
We are interested in understanding how CD8 T cell responses are organised in space and time to achieve the correct balance between tolerance and immunity.
How cells collectively maintain the integrity of an organ, system or organism is a fundamental question in biology. This has been particularly elusive in the context of the immune system where the cell types and signals involved are dynamic and widely spread throughout the body.
Despite a remarkable degree of plasticity, stochasticity and functional heterogeneity in their individual response, T cell overall response to infection is consistent and robust. This implies a coordinated response across a system-wide level to facilitate the control of pathogens while maintaining self-tolerance. Much research has focused on individual T cell activation and differentiation, but how the stochastic individual responses are integrated is unknown. This global coordination can only be achieved by constant cellular communication between responding cells and has to be supported by the ecosystem they reside in. This is the focus of our research, which is articulated around three main avenues:
1. CD8 T CELL COMMUNICATION IN INFECTION.
We are interested in the cellular communications that regulate the collective behaviour of CD8 T cells. We previously discovered that CD8 T cells interact with each other, forming T cell–T cell synapses driven by the integrin LFA-1 and its ligand ICAM-1. T cell synapses regulate T cell differentiation (Gérard et al, Nature Immunology 2013). We are now investigating how direct communication between CD8 T cells (Uhl et al, IJMS 2020) shapes the breadth of T cell responses and which signals are involved, currently focusing on IFN-gamma signalling (Krummel, Mahale et al, PNAS 2018, Uhl et al, Nat Comms 2023). To address this question, we use a combination of imaging, functional assays and genomics.
2. IMMUNE FEEDBACKS IN TUMOURS.
Our lab studies how cancer co-opt physiological regulatory mechanisms to evade the immune responses (Headley et al., Nature 2016). Using functional assays and genomics, we are addressing how pro-inflammatory cytokines regulate anti-tumour responses. Pro-inflammatory cytokines, such as IFN-gamma, are central to anti-tumour immunity. But it also signals to other cells in the tumour microenvironment, where it displays anti- but also pro-tumour functions. For example, we demonstrated that IFN-gamma signalling in T cells restricts anti-tumour immunity by inhibiting the maintenance and diversity of intra-tumoural stem-like T cells (Mazet et al., Nat Comms 2023). We are currently investigating how the immune response responds and adapt to tumours that are escaping immunosurveillance by inhibiting IFN-gamma sensing.
3. MICROENVIRONMENTS AND COLLECTIVE BEHAVIOUR.
We previously found that T cells display discrete migration patterns allowing for both exploration of a large territory and efficient scanning of potential antigen-presenting cells (APCs) (Gérard et al, Cell 2014). Once T cells get primed, they form long lasting contacts with APCs but they also get influenced by the microenvironment they reside in. Using imaging, we are studying the contrasting microenvironments T cells join during infection (Krummel, Mahale et al, PNAS 2018; Mazet et al, Jove 2019). Similarly, we are investigating the microenvironments where T cells are found in tumours, and how tumour sensitivity to immune mediators affects immune microenvironments and subsequent T cell responses.