Ribot & Silva-Santos Lab

Neuro-Immunology & Immuno-Oncology

Research developed in the Julie Ribot & Bruno Silva-Santos Joint lab, based on Cellular and Molecular Immunology, chases fundamental questions related to the biology of white blood cells (leukocytes). Two main research programs are running by two independent and cooperative group leaders:

Neuro-Immunology, run by Julie Ribot, that aims to dissect neuro-immune crosstalks, for example by considering the pathophysiological contributions of IL-17 beyond immune surveillance; and Immuno-Oncology, run by Bruno Silva-Santos, that investigates cellular and molecular interactions within the tumor microenvironment, with a focus on gamma-delta (γδ) T cells.

Neuro-Immunology

We are currently witnessing the emergence of a body of evidence that document novel functions of the immune system, interacting with other complex organ systems to maintain tissue homeostasis independently of pathogen challenge. Recent advances have now provided key findings that the immune system also acts as a tissue rheostat that continually senses homeostatic perturbations and contributes to organ steady state physiology.

We have recently identified a population of γδ T cells that infiltrate the lymphatics within the dura matter of the brain meninges. We demonstrated that this subset is a major source of IL-17, which promotes short-term memory by increasing neuronal synaptic plasticity in the hippocampus. On the other hand, we further reported a significant increase of meningeal IL-17 producing cells, which triggers the onset of cognitive decline in a mouse model of Alzheimer’s Disease. We thus postulate a dual role for IL-17: pro-cognitive at steady state and anti-cognitive in the context of neurodegeneration, and highlight that a tight regulation of the levels of meningeal IL-17 is critical to maintain brain integrity. These considerations led us to raise neuroscience questions under an innovative immunological angle:

• How are IL-17 levels finely tuned to guarantee optimal cognitive functions?

We are assessing the impact of environmental cues using diverse approaches such as system pharmacological manipulation, surgical ablation and specific genetic mouse models. As experimental read-out, we mostly use flow cytometry to analyze tissue immune landscape (focusing on IL-17 producers), as well as RNA sequencing to pioneer subset transcriptional profiling at single-cell resolution.

• What is the impact of IL-17 regulation on tissue pathophysiology?

We are unveiling novel neurophysiological processes under the regulation of IL-17 in the central and peripheral nervous system, namely focusing on learning and memory, anxiety, sleep and nerve regeneration. For this, we use genetic mouse models, microscopy, behavioral assays and electrophysiology.

Immuno-Oncology

In our Immuno-Oncology research line, which has been funded by the “la Caixa” Foundation, the European Molecular Biology Organization and Fundação para a Ciência e a Tecnologia, we study cellular and molecular crosstalks within the tumor microenvironment (TME), trying to boost anti-tumor mechanisms (based on cytotoxicity and interferon-gamma secretion) over pro-tumor effects (linked to inflammation and angiogenesis). Moreover, we have translated the seminal knowledge we produced on gamma-delta (γδ) T cells to the development of a new methodology for adoptive cell therapy of cancer – Delta One T (DOT) cells – within a spin-off company, Lymphact SA, acquired in 2018 by GammaDelta Therapeutics (London, UK), and now part of the Takeda immunotherapy portfolio. In our team, we continue to study DOT cells, their functional regulation and their molecular mechanisms of tumor cell recognition, in collaboration with Takeda.

We also conduct a more fundamental Immuno-Biology research line, which has been funded by Starting and Consolidator Grants from the European Research Council (ERC),where we focus on the thymic development and functional differentiation of gamma-delta (γδ) T cells. We aim to identify new molecular mechanisms involved in their thymic generation and in peripheral immune responses to infections (such as malaria) and cancer.