The goal of this project is to determine the role of a poorly studied calcium channel subunit in T lymphocytes (T cells) and immune responses. T cells are white blood cells that play a critical role during viral infection by killing virus-infected cells and promoting the production of virus-neutralizing antibodies. The function of T cells depends on calcium channels that form pores in the cell membrane and facilitate the influx of calcium into cells. Inside cells, calcium functions as a signaling molecule that binds to various proteins and promotes the activation of T cells, for instance by regulating the expression of immune modulatory genes. Our lab has extensively studied the function of calcium channels called CRAC channels that are encoded by ORAI and STIM genes. Recent reports suggest that other calcium channels may also mediate calcium influx and T cell function. Among those channels are voltage-gated calcium channels, which are well studied in the heart and brain where they regulate cell function in response to electrical stimulation. The gene studied in this proposal is CACNB1, which encodes one of four known regulatory subunits of voltage-gated calcium channels. CACNB1 is critical for different aspects of channel function including channel trafficking, activation and inactivation. Past research on CACNB1 has focused on excitable cells such as neurons, but CACNB1 is also expressed in T cells, where its role in immune responses remains unknown. Recently, genetic studies of two pore-forming subunits of voltage-gated calcium channels and several regulatory subunits have shown altered function of T cells that lack these channel subunits or express mutant forms. In particular, mutation of the regulatory CACNB2, B3 and B4 genes were reported to affect T cells development in the thymus and homeostasis in the spleen. The role of CACNB1 in T cells has not been investigated yet although it is the most highly expressed of the four regulatory subunits in T cells. Overall, the role of voltage-gated calcium channels in T cells and immune responses remains disputed, which in part is due to their unclear activation mechanism in T cells, which are not electrically excitable. We recently identified CACNB1 in a functional genomics screen in live mice as one of several ion channels that regulates the growth of T cells in response to viral infection of mice. In this application, we propose to further characterize the role of CACNB1 in T cell function and immune responses. Specifically, we will study how deletion of CACNB1 affects calcium signaling, calcium channel function and the ability of T cells to grow, produce immune modulatory cytokines and kill virus-infected cells. Furthermore, we will investigate the consequences of CACNB1 deficiency for immunity to infection by infecting mice whose T cells lack CACNB1 with viruses and analyzing their immune responses. The proposed research will shed new light on the function of CACNB1 and voltage-gated calcium channels in T cells and immune responses. CACNB1 is the most highly and specifically expressed regulatory subunit in T cells and may represent a new drug target for the treatment of autoimmunity and inflammation.
T lymphocytes play an important role in immune responses to infections and tumors, and they mediate inflammation in a variety of autoimmune diseases. The function of T cells depends on calcium channels, which facilitate the movement of calcium across the cell membrane, and recent reports suggest that specific calcium channels that are well studied in the heart and brain may also play a role in T cell function. The aims of this project are to determine the role of a poorly studied calcium channel subunit in T cell-mediated immune responses with the ultimate goal to evaluate it as a new ion channel drug target for the treatment of autoimmunity and inflammation.
