Heat (bottom)-induced increases in ICAM-1 and CCL21 increase trafficking to lymph nodes.


“In whatever part of the body there is a sweat, it shows that the disease is seated there,” said Hippocrates. Now, Qing Chen, Sharon Evans (Roswell Park Cancer Institute, Buffalo, NY), and colleagues find that fever turns on homing molecules that direct lymphocytes into lymph nodes. The increased trafficking through lymph nodes should increase the chance of a lymphocyte encountering and being activated by its target antigen-presenting cell.

Higher temperatures are known to be beneficial for postinfection survival. Cold-blooded animals do better if they can seek out the sun when infected. Infected warm-blooded animals incur a 15% increase in metabolic cost for every 1°C rise in core temperature, suggesting that the benefit may be equally high.

The most obvious response to fever is that vasodilation (an attempt to cool down the body) increases blood flow, thus increasing the sheer number of cells that pass by high endothelial venules (HEVs), the entry gates to lymph nodes. “If anybody thinks of fever at all, they think of it in those terms,” says Evans. “But we think there is an additional change besides the physics.”

Evans turned up the temperature to 39.5°C, and then returned it to normal before the experiment began so that blood flow effects were eliminated. Her team found that the initial rolling interaction of lymphocytes on HEVs was unchanged, but two key downstream molecules were up-regulated. The CCL21 chemokine and ICAM-1 adhesion molecule (both on HEVs) mediate a post-rolling arrest that is required for entry through HEVs, and lumenal presentation of both was increased up to twofold by the prior increase in temperature.

IL-6 signaling is required for the heat-induced up-regulation of the trafficking and ICAM-1 but not of CCL21. It is not yet clear what turns on IL-6 or what makes the signaling so specific to HEVs.

The fever signal might be particularly useful when there is a rare antigen or when a previously localized infection spreads. So should we all suffer through our fevers rather than combat them with drugs? “I'm the biggest hypocrite,” says Evans. “If I don't feel well I take a Tylenol.” She says the study has important clinical implications, but for most people “if we take a Tylenol it's not going to be the deciding factor.”


Chen, Q., et al.
Nat. Immunol.