CAMuS

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which represents a major public health issue as current treatments do not prevent neurodegeneration. During MS, CD8+ T cells and T helper (Th1/Th17) CD4+ T cells actively participates to inflammatory CNS pathology. After crossing the blood brain barrier, T cells are trapped in the perivascular space where contact mediated signals with astrocytes regulate trafficking and immune-modulatory pathways critical to CNS neuro-inflammation. Literature shows that Notch signaling regulates T cell subset development, promoting autoimmunity in experimental autoimmune encephalomyelitis (EAE). Interestingly, we showed that the Notch ligand, Delta like 4 (Dll4), is upregulated in reactive astrocytes and sustains astrogliosis in EAE and MS. We now hypothesize that astrocytic Dll4 interacts with its receptors Notch1 and 2 on infiltrated T cells to control subset function during neuropathology. Aim1 and 2 test if reactive astrocytes use Dll4 to control perivascular and parenchymal immune cell function in acute and progressive phases of EAE and in MS. The project combines expertise of C. Chapouly in neurovascular biology with these of A. Astier and R. Liblau in immunology. The methodology relies on (1) mice knockout for Dll4 in astrocytes induced with EAE to study relapses and secondary progression, (2) co-cultures of human T cells (from constituted biobanks) with human astrocytes and (3) CNS tissues from person with MS versus non pathological CNS tissues. The project relies on cutting edge technologies such as FACS (17-color standardized panels), RNAseq and spatial transcriptomics combined with more traditional analysis. Overall, our project aims to understand how acute neuro-inflammatory changes prime the CNS for subsequent injury or repair in order to identify novel translational strategies for MS pathology.