Cyclic GMP-AMP synthase regulates the development of experimental autoimmune encephalomyelitis

Our immune system is composed of two arms, namely the innate immune system and the adaptive immune system. Upon attack by pathogens, the innate immune system is the first to engage with a rapid, but somewhat non-specific response. This is followed by activation of the adaptive immune responses which is highly specific, and efficient at eliminating invading pathogens. Within the adaptive immune system, T lymphocytes are the key effector cells which direct and regulate immunity. Importantly, T lymphocytes are alerted to the presence of pathogens by a key cell from the innate immune system termed dendritic cells. The dendritic cell population has the capacity to ingest pathogens, process their proteins and present them to T lymphocytes resulting in activation of the latter. In order for dendritic cells to complete this process, they must recognize the foreign nature of ingested pathogens. This recognition is carried out by a number of cytosolic receptors including Cyclic GMP-AMP synthase (cGAS). Specifically, cGAS can bind to DNA derived from bacteria and viruses which then stimulates the dendritic cells to execute the activation of T lymphocytes. Although this is understood, it is unclear to what extent cGAS can regulate the full activation of T lymphocytes when responding to foreign pathogens or when driving an aberrant response against self-proteins (autoimmune reactions). To explore this question, experiments in this thesis examined the role of cGAS in an experimental version of multiple sclerosis, an autoimmune disease where T lymphocytes attack the insulating covers of nerve cells within the brain and spinal cord leading to a range neurological symptoms. The mouse-based version of multiple sclerosis is termed Experimental Autoimmune Encephalomyelitis (EAE) and is well understood to be driven by self-reactive T lymphocytes. Studies therefore examined whether EAE is fully induced when cGAS is absent in all cells of the (mouse) body, absent only in T lymphocytes or absent in dendritic cells. The results demonstrated the need for cGAS to be present in dendritic cells but not T lymphocytes, in order to induce the disease. These findings further our knowledge regarding the role of cGAS in activating T lymphocytes, and may provide insights into novel therapeutic approaches to treat multiple sclerosis.