Project Summary A variety of deadly pathogens cause disease by triggering excessive inflammation and the release of a storm of pro-inflammatory host molecules. This host “cytokine storm” is responsible for the severity of symptoms and ultimately for the death of the host. Regulatory cells of the immune system normally work to prevent inflammation and this life-threatening cytokine storm. Treatment options for these infections are limited, in part due to our lack of understanding of how the cytokine storm develops and why the immune system fails to control the inflammatory response. The overarching hypothesis for our research program is that an immunotherapy designed to activate regulatory immune cells will restrict the cytokine storm. Testing this requires an understanding of how regulatory cells modulate the cytokine storm in a natural infection. Published studies found that natural killer T (NKT) cells, a population of white blood cells displaying both pro-inflammatory and regulatory functions, contributed to the cytokine storm. This was very surprising since, in our preliminary studies, NKT cells suppress the cytokine storm. Initially, this dichotomy was difficult to explain until a recent publication documented differences in tissue distribution for subsets of NKT cells. This allowed us to hypothesize that the two subsets of NKT cells not only have different tissue distributions but also have opposing roles in regulating the cytokines storm. Therefore, the goal of this project is to understand how NKT cell subsets function in regulating the cytokine storm and whether one of the NKT cell subsets could be a potential target for immunotherapy. To achieve this goal, this research project will test the hypothesis that type I and II NKT cell subset(s) having opposing roles in regulating the cytokine storm and development of disease. Furthermore, we will determine the mechanism of action by which regulatory NKT cells modulate the production of cytokine storm cytokines (IL-6, IL-1β). Initially, we will use a cell culture system to investigate this mechanism using mouse and human cells. Ultimately, however, animal models will be required to compare the cytokine storm response in infected mice that have an adequate NKT response and those that lack these mechanisms. Successful completion of these studies will not only determine which NKT cell subset contributes/regulates disease and the mechanism by which this modulation occurs but will also allow us to determine whether NKT cell subsets could be a potential target for future development of immunotherapies to treat the cytokine storm. If successful, future studies will explore these novel therapies and whether this is a general mechanism relevant to all cytokine storm-causing infections.

Project Narrative A variety of NIH Priority Pathogens cause disease through triggering an uncontrolled inflammatory response, termed the cytokine storm. Treatment options for these diseases are limited, in part, due to our lack of understanding of how the cytokine storm develops and why the immune system fails to control the inflammatory response. The overarching hypothesis for our research program is that stimulating the activity of regulatory immune cells will restrict the cytokine storm and this proposal is designed to determine a potential regulatory mechanism for this control.