The goal of this application is to identify novel ion channels that regulate the function of T lymphocytes. T cells play an important role in immune responses to infection and mediate inflammation in a variety of autoimmune diseases. The function of T cells has been reported to depend on ion channels that control their development, proliferation and effector functions. More than 600 ion channels and associated proteins regulate the movement of a ions, including calcium, magnesium, zinc, potassium, sodium and chloride, across lipophilic cell membranes. The role of ion channels is well studied in cells of the nervous and cardiovascular system or the kidney. By comparison, relatively little is known about ion channels in the immune system and how they regulate normal immunity to infection or abnormal immune responses in allergy or autoimmune diseases. Of the more than 600 known ion channels and associated proteins, only 8-10 are well established to regulate the function of T cells based on genetic evidence in humans and mice. This is a major gap in our knowledge of T cell physiology and the regulation of T cell immunity. We therefore propose to analyze novel ion channels that have not been associated with T cell function before and that we found to be highly and differentially expressed in human and mouse T cells based on comparative bioinformatics analyses. We furthermore propose to conduct a functional genomics screen to identify novel ion channels that regulate T cell function in the context of viral infection in vivo. A systematic analysis of ion channels in T cell or other immune responses has never been done. This striking void at the interface of immunology and physiology represents a discovery opportunity to define ion channels that regulate T cell mediated immunity to infection and autoimmunity. From a translational perspective, ion channel inhibitory drugs have successfully been used to treat diseases of the cardiovascular and nervous systems, proving the usefulness of ion channels as drug targets. The identification of novel ion channels that control T cell immunity has significant therapeutic potential for the treatment of immune diseases. Such ion channels would be promising drug targets for the treatment of T cell-mediated immune diseases such as autoimmune disorders or allergy or for the modulation of T cell function in antitumor immunity. Although our initial screen will focus on ion channels that regulate CD4+ T cell-mediated immunity to infection, future screens using similar approaches will be designed to identify ion channels that control the function of T cells in autoimmunity and antitumor immunity. Beyond the immune system, the screening approach we propose here can be applied to identify novel ion channels that regulate the function of many other tissues and cell types. The reagents, data and experience gathered through this R21 grant will open new research avenues for our lab and lead to future R01 grant applications.
T lymphocytes play an important role in immune responses to infections and mediate inflammation in a variety of autoimmune diseases. Ion channels facilitate the movement of ions such as calcium, magnesium, sodium or potassium across cell membranes and are important and well-studied regulators of cell function in many tissues and cell types. In T lymphocytes and other immune cells, their role is less well understood, and the aim of this proposal is to identify and characterize novel ion channels that regulate T lymphocyte function with the longterm goal to find ion channel targets for the treatment of autoimmune diseases.
|Vaeth, Martin; Yang, Jun; Yamashita, Megumi et al. (2017) ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. Nat Commun 8:14714|