ATP1B3: novel regulator of T cell-mediated immunity

Project Summary T cells are key components of immune responses to infection and in autoimmunity. Like all cells, they require ion channels and transporters for their function. Channels move ions such as calcium, sodium and potassium across lipid membranes to maintain ion gradients, facilitate signal transduction and influence many cellular processes. Several channels are known to play critical roles in immune cells. In general, however, only a small number of the known hundreds of channels have been studied in T cells. This is a major gap in our understanding of T cell biology and the mechanisms underlying T cell-mediated immune responses. From a clinical perspective, ion channels are excellent drug targets as is evident from the fact that many channel blockers are used for the treatment of cardiovascular and neuropsychiatric disorders. There are currently no FDA-approved drugs targeting ion channels for the treatment of autoimmune and inflammatory diseases. To address this gap in knowledge and missed opportunity for drug discovery, we conducted functional genetics screens to identify hitherto unrecognized ion channels that control T cell function in the context of infection and autoimmunity. Some of the strongest and least understood channel-related genes to emerge from these screens were components of the sodium-potassium ATPase. This multiprotein complex is located in the cell membrane and uses ATP as energy source to pump sodium ions out of cells in exchange for potassium ions that go in. In neurons, this complex is essential for electrical excitability and in the heart for the ability of muscle fibers to contract. In T cells, by contrast, the function of the sodium-potassium ATPase and its role in immune responses to infection and autoimmunity are almost completely unknown. We identified four subunits of the sodium-potassium ATPase in our screens and confirmed that two of them in particular are required for the antigen-driven expansion of T cells in vivo. This expansion of T cells during infection or in autoimmune diseases is an essential hallmark of adaptive immunity. Our data show that deletion of ATP1B3, one of the subunits of the sodium-potassium ATPase we identified, almost completely suppresses T cell expansion and disease in a preclinical model of multiple sclerosis, an autoimmune disease in which T cells promote inflammation and destruction of the brain. Additional data generated by using unbiased transcriptomic and metabolomics approaches point to a role of ATP1B3 and the sodium-potassium ATPase in regulating the cell cycle and metabolism of T cells. In this proposal, we will determine how ATP1B3 regulates the function of the sodium-potassium ATPase in T cells, investigate the signaling and metabolic mechanisms by which ATP1B3 controls T cell function, and determine how ATP1B3 regulates T cell-mediated immune responses and its suitability as a drug target in autoimmunity.