Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37.

Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57+ FcεRγ-NKG2C+ adaptive (CD56+CD3-) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNγ production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNγ production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy. Cancer Immunol Res; 6(7); 766-75. ©2018 AACR.

Temperature effects on the activity, shape, and storage of platelets from 13-lined ground squirrels.

The objective of this study is to determine how a hibernating mammal avoids the formation of blood clots under periods of low blood flow. A microfluidic vascular injury model was performed to differentiate the effects of temperature and shear rate on platelet adhesion to collagen. Human and ground squirrel whole blood was incubated at 15 or 37 °C and then passed through a microfluidic chamber over a 250-µm strip of type I fibrillar collagen at that temperature and the shear rates of 50 or 300 s-1 to simulate torpid and aroused conditions, respectively. At 15 °C, both human and ground squirrel platelets showed a 90-95% decrease in accumulation on collagen independent of shear rate. At 37 °C, human platelet accumulation reduced by 50% at 50 s-1 compared to 300 s-1, while ground squirrel platelet accumulation dropped by 80%. When compared to platelets from non-hibernating animals, platelets from animals collected after arousal from torpor showed a 60% decrease in binding at 37 °C and 300 s-1, but a 2.5-fold increase in binding at 15 °C and 50 s-1. vWF binding in platelets from hibernating ground squirrels was decreased by 50% relative to non-hibernating platelets. The source of the plasma that platelets were stored in did not affect the results indicating that the decreased vWF binding was a property of the platelets. Upon chilling, ground squirrel platelets increase microtubule assembly leading to the formation of long rods. This shape change is concurrent with sequestration of platelets in the liver and not the spleen. In conclusion, it appears that ground squirrel platelets are sequestered in the liver during torpor and have reduced binding capacity for plasma vWF and lower accumulation on collagen at low shear rates and after storage at cold temperatures, while still being activated by external agonists. These adaptations would protect the animals from spontaneous thrombus formation during torpor but allow them to restore normal platelet function upon arousal.