Exploring the VISTA of glial cells:astrocytes and microglia from development to disease

Multiple sclerosis (MS) is a chronic and often progressive disease of the central nervous system (CNS), which manifests at a young age. In MS, immune cell types including macrophages and lymphocytes enter the CNS and damage the myelin sheath, which acts as an insulation for axons and is crucial for rapid saltatory action potential propagation, and myelin damage also results in axonal loss. Immune checkpoints are receptors that provide a balance between enhancing and limiting the immune response to allow proper protective function without aberrant inflammation or autoimmune disease. Modulating immune checkpoint activity is a powerful tool to, for example, increase the immune response against cancer, or to reduce the immune response in autoimmune diseases. VISTA is an immune checkpoint that provides inhibitory signals to T cells leading to reduced immunity. Therefore, enhancing VISTA signaling in MS offers a novel treatment strategy to limit autoimmunity and reduce symptoms. In this thesis, the function of VISTA was investigated in CNS-resident cells, to explore the therapeutic potential of VISTA for MS. VISTA plays a role in the function of microglia, which are CNS-resident immune cells. Microglia have diverse functions in the CNS such as protection from intruders (e.g. bacteria and viruses), support of neurons, and tissue regeneration. In MS, microglia are involved in the anti-myelin immune response, but also in wound healing. VISTA regulates microglia uptake of myelin and microglia homeostasis. In conclusion, modulating VISTA signaling may present a novel strategy to treat MS, which likely affects CNS-resident cells