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.

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

Natural killer (NK) cell maturation is a tightly controlled process that endows NK cells with functional competence and the capacity to recognize target cells. Here, we found that the transcription factor (TF) Zeb2 was the most highly induced TF during NK cell maturation. Zeb2 is known to control epithelial to mesenchymal transition, but its role in immune cells is mostly undefined. Targeted deletion of Zeb2 resulted in impaired NK cell maturation, survival, and exit from the bone marrow. NK cell function was preserved, but mice lacking Zeb2 in NK cells were more susceptible to B16 melanoma lung metastases. Reciprocally, ectopic expression of Zeb2 resulted in a higher frequency of mature NK cells in all organs. Moreover, the immature phenotype of Zeb2^−/− NK cells closely resembled that of Tbx21^−/− NK cells. This was caused by both a dependence of Zeb2 expression on T-bet and a probable cooperation of these factors in gene regulation. Transgenic expression of Zeb2 in Tbx21^−/− NK cells partially restored a normal maturation, establishing that timely induction of Zeb2 by T-bet is an essential event during NK cell differentiation. Finally, this novel transcriptional cascade could also operate in human as T-bet and Zeb2 are similarly regulated in mouse and human NK cells.

T‐bet and Eomes are T‐box transcription factors that drive the differentiation and function of cytotoxic lymphocytes such as NK cells. Their DNA‐binding domains are highly similar, suggesting redundant transcriptional activity. However, while these transcription factors have different patterns of expression, the phenotype of loss‐of‐function mouse models suggests that they play distinct roles in the development of NK cells and other innate lymphoid cells (ILCs). Recent technological advances using reporter mice and conditional knockouts were fundamental in defining the regulation and function of these factors at steady state and during pathological conditions such as various types of cancer or infection. Here, we review these recent developments, focusing on NK cells as prototypical cytotoxic lymphocytes and their development, and also discuss parallels between NK cells and T cells. We also examine the role of T‐bet and Eomes in human NK cells and ILC1s. Considering divergent findings on mouse and human ILC1s, we propose that NK cells are defined by coexpression of T‐bet and Eomes, while ILC1s express only one of these factors, either T‐bet or Eomes, depending on the tissue or the species.

TLR have a crucial role in the detection of microbial infection in mammals. Until recently, most investigations on TLR have focused on cells of the innate immune system and on the role of TLR in the initiation of antigen‐specific responses following recognition of microbial products by APC. Here, we report that murine T cells express TLR1, TLR2, TLR6, TLR7 and TLR9 mRNA. Using CD8 T cells from F5 TCR‐transgenic mice, we demonstrate that the lipopeptide Pam₃CysSK₄ (Pam), a synthetic analog of bacterial and mycoplasmal lipoproteins that recognizes TLR1/2 complex, costimulates antigen‐activated T cells. Costimulation with Pam permits an increased cell proliferation and survival associated with a sustained CD25 expression and an enhanced expression of Bcl‐xL anti‐apoptotic protein. In addition, we show that costimulation with Pam up‐regulates IFN‐γ production but also granzyme B secretion and cytotoxic activity of antigen‐activated T cells, indicating that TLR2 engagement enhances the major effector functions of CD8 T cells. Finally, we demonstrate that TLR2 engagement on T cells lowers the activation threshold for costimulatory signals delivered by APC.