When T cells recognize a dangerous pathogen, they kick into gear and attack. One crucial step in the activation of these immune cells involves a protein receptor called CRAC opening and allowing calcium ions to rush inside the cells. Or so scientists thought. A research team led by Wilfred A. Jefferies of the University of British Columbia and Eyal Raz of the University of California, San Diego, has demonstrated that another receptor, TRPV1, also helps spur T cells into action (Nat. Immunol. 2014, DOI: 10.1038/ni.3009). Not normally associated with the immune system, TRPV1 is well-known for its role in pain sensing: The receptor becomes active and sends distress signals to the brain in response to heat and the chili pepper compound capsaicin. Using electrophysiology, genetic engineering, and other tools, Jefferies, Raz, and coworkers have shown that TRPV1 regulates T cell calcium ion influx. When the experimental cinnamide compound SB366791 blocked TRPV1 in mice afflicted by colitis, the inflammation in their gut walls declined. Because SB366791 worked at a low dose, Raz says the team’s discovery might mean a second chance for TRPV1 blockers: as autoimmune disease therapies. Tested in humans as painkillers, some of these compounds have caused side effects such as fevers at high doses.