Abstract
Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease.
Highlights
Lymphocytes become pathogenic when tolerance to self-tissues is lost, often resulting in the onset of autoimmune disease
In contrast to the defects in thymocyte number, the percentage and number of B220+ and CD3+ cells in the spleen of Itpkbfl/fl are unchanged (Fig 1C and 1D). These results contrast with dramatic loss of mature T cells observed in MsTless mice and suggests that inositol trisphosphate 3’ kinase B (Itpkb) is not required for mature lymphocyte survival and homeostasis at this time point
Utilizing an inducible Itpkb knockout, the current study demonstrates a key role for the inositol kinase, Itpkb, and its product, Ins(1,3,4,5) P4, in blocking mature T lymphocyte death via the inhibition of components of the calcium-release activated calcium (CRAC) machinery, Orai1 and stromal interaction molecule 1 (Stim1)
Summary
Lymphocytes become pathogenic when tolerance to self-tissues is lost, often resulting in the onset of autoimmune disease. Receptors that trigger immune cell activation are linked to phosphorylation events mediated by kinases, which has led to the idea that blocking kinases involved in cell activation with low molecular weight inhibitors (LMW) may be an effective way to treat autoimmune disease. Several kinase inhibitors are currently in clinical trials for numerous autoimmune indications, such as rheumatoid arthritis, inflammatory bowel disease, PLOS ONE | DOI:10.1371/journal.pone.0131071. Itpkb Controls Autoimmunity via Ca2+-Induced T Cell Death manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
