Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells.

Circulating NK cells normally experience temperature gradients as they move about the body, but the onset of inflammation can expose them and their targets to febrile temperatures for several hours. We found that exposure of human peripheral blood NK cells and target cells to fever-range temperatures significantly enhances lysis of Colo205 target cells. A similar effect was not observed when NK cell lines or IL-2-activated peripheral blood NK cells were used as effectors, indicating that thermal sensitivity of effectors is maturation or activation state-dependent. Use of blocking antibodies revealed that this effect is also dependent on the function of the activating receptor NKG2D and its ligand MHC class I-related chain A (MICA). On NK cells, it was observed that thermal exposure does not affect the total level of NKG2D surface expression, but does result in its distinct clustering, identical to that which occurs following IL-2-induced activation. On tumor target cells, a similar, mild temperature elevation results in transcriptional up-regulation of MICA in a manner that correlates with increased sensitivity to cytolysis. Overall, these data reveal that NK cells possess thermally responsive regulatory elements, which facilitate their ability to capitalize on reciprocal, stress-induced changes simultaneously occurring on target cells during inflammation and fever.