Our research also focuses on the regulation of a potassium channel, KCa3.1, and its role in the activation of T and B lymphocytes. KCa3.1 is required for calcium influx in a subset of T and B lymphocytes, which is critical for the subsequent activation these cells. Due to the importance of KCa3.1 in the activation of immune cells, inhibitors of KCa3.1 have been proposed to treat autoimmune diseases such as systemic lupus erythematosus and asthma, and to prevent rejection of transplanted organs, underscoring the importance in understanding how these channels are regulated.
We recently identified several new molecules in T and B cells that either positively or negatively regulate KCa3.1 channel activity and, via their effects on KCa3.1, either positively or negatively regulate activation of these cells. One example of a signaling protein that we have identified that is required in KCa3.1 channel activity is nucleoside diphosphate kinase B (NDPK-B).
We found that NDPK directly phosphorylates and activates KCa3.1 channel activity and is required for the subsequent activation T and B lymphocytes. More recently, studying KCa3.1 knockout mice, we found that while loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca2+ influx and cytokine production were markedly impaired in KCa3.1 knockout Th1 and Th2 CD4 T cells. Moreover, KCa3.1 knockout mice were protected from developing severe colitis in two mouse models of inflammatory bowel disease (IBD). Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with IBD.