Blocking TGF-β signaling in natural killer cells enhances their metabolism and ability to kill tumor cells.

The kinase mTOR is important in lymphocyte bioenergetics but has not been examined in natural killer cells. Walzer and colleagues demonstrate that mTOR is key to sustaining the proliferation and effector function of these cells. Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings.

Trail⁺DX5⁻Eomes⁻ natural killer (NK) cells arise in the mouse fetal liver and persist in the adult liver. Their relationships with Trail⁻DX5⁺ NK cells remain controversial. We generated a novel Eomes-GFP reporter murine model to address this question. We found that Eomes⁻ NK cells are not precursors of classical Eomes⁺ NK cells but rather constitute a distinct lineage of innate lymphoid cells. Eomes⁻ NK cells are strictly dependent on both T-bet and IL-15, similarly to NKT cells. We observed that, in the liver, expression of T-bet in progenitors represses Eomes expression and the development of Eomes⁺ NK cells. Reciprocally, the bone marrow (BM) microenvironment restricts T-bet expression in developing NK cells. Ectopic expression of T-bet forces the development of Eomes⁻ NK cells, demonstrating that repression of T-bet is essential for the development of Eomes⁺ NK cells. Gene profile analyses show that Eomes⁻ NK cells share part of their transcriptional program with NKT cells, including genes involved in liver homing and NK cell receptors. Moreover, Eomes⁻ NK cells produce a broad range of cytokines, including IL-2 and TNF in vitro and in vivo, during immune responses against vaccinia virus. Thus, mutually exclusive expression of T-bet and Eomes drives the development of different NK cell lineages with complementary functions.

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, becausein vivotests have a suboptimal sensitivity and can be time‐consuming, expensive and potentially risky, especially drug provocation tests. There are several currently availablein vitromethods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of thesein vitromethods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types ofDHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the availablein vitromethods forDHRdiagnosis. We have found that although there are manyin vitrotests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well‐controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently availablein vitrotests in a large series of well‐characterized patients withDHRand to develop new tests for diagnosis.