Jakob H. von Moltke
Immune Responses to Parasitic Worms and Allergens
The mammalian immune system encounters an enormous diversity of foreign stimuli, including viruses, bacteria, protozoa, parasitic worms (helminths), and allergenic particles. Determining how these stimuli are sensed and distinguished is fundamental to our understanding of the immune response and accordingly to our therapeutic interventions. The discovery of Toll-like receptors in the 1990s established the paradigm that specific microbial ligands are detected by matching immune receptors. Many ligand-receptor pairs have since been identified, and our understanding of bacterial and viral "type 1" detection is quite advanced. By contrast, very little is known about how the immune system first senses helminths and allergens, which give rise to a "type 2" immune response. Indeed, it has not even been clear which cells first detect type 2 stimuli, let alone the underlying mechanisms.
We and others recently discovered that the immune response to intestinal helminth infection requires a specialized epithelial lineage known as the tuft cell. We believe these cells represent the missing link in initiation of type 2 inflammation. Tuft cells physically bridge the divide between helminths in the intestinal lumen and immune cells in the underlying tissue, and encode a chemical sensing pathway that we found is required for intestinal type 2 immune responses. The immediate goals of our laboratory are to determine how intestinal tuft cells detect helminth infection and how they regulate the downstream changes in intestinal physiology that are a hallmark of type 2 immunity. In the longer term, we will study the immune detection of allergens and use tuft cells as an entry point to study interactions of the immune and nervous systems.
Our work represents an entirely new strategy for understanding type 2 immune responses, and uses creative experimental approaches to finally answer a fundamental question: how are helminths sensed by the immune system? Although focused on helminth infection, this work may provide insights into the detection of allergens and other type 2 agonists as well. Our findings could therefore uncover novel therapeutic targets for treating both helminths, which infect billions worldwide, and allergic inflammation, which represents an emerging epidemic.