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.
Patrolling Ly6C− monocytes are blood‐circulating cells that play a role in inflammation and in the defense against pathogens. Here, we show that similar to natural killer (NK) cells, patrolling ...monocytes express high levels of S1PR5, a G‐coupled receptor for sphingosine‐1 phosphate. We found that S1pr5−/− mice lack peripheral Ly6C− monocytes but have a normal number of these cells in the bone marrow (BM). Various lines of evidence exclude a direct contribution of S1PR5 in the survival of Ly6C− monocytes at the periphery. Rather, our data support a role for S1PR5 in the egress of Ly6C− monocytes from the BM. In particular, we observed a reduced frequency of patrolling monocytes in BM sinusoids of S1PR5 KO mice. Unexpectedly, S1P was not a chemoattractant for patrolling monocytes and had no significant effect on their viability in vitro. Moreover, the disruption of S1P gradients in vivo did not alter Ly6C− monocyte trafficking and viability. These data suggest that S1PR5 regulates the trafficking of monocytes via a mechanism independent of S1P gradients.
Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with ...leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4(+) T cells, Ly6C(+) monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.
During development, natural killer (NK) cells exit the BM to reach the blood. CXCR4 retains NK cells in the BM, whereas the sphingosine-1 phosphate receptor 5 (S1P5) promotes their exit from this ...organ. However, how the action of these receptors is coordinated to preserve NK-cell development in the BM parenchyma while providing mature NK cells at the periphery is unclear. The role of CXCR4 and S1P5 in NK-cell recirculation at the periphery is also unknown. In the present study, we show that, during NK-cell differentiation, CXCR4 expression decreases whereas S1P5 expression increases, thus favoring the exit of mature NK cells via BM sinusoids. Using S1P5−/− mice and a new knockin mouse model in which CXCR4 cannot be desensitized (a mouse model of warts, hypogammaglobulinemia, infections, and myelokathexis WHIM syndrome), we demonstrate that NK-cell exit from the BM requires both CXCR4 desensitization and S1P5 engagement. These 2 signals occur independently of each other: CXCR4 desensitization is not induced by S1P5 engagement and vice versa. Once in the blood, the S1P concentration increases and S1P5 responsiveness decreases. This responsiveness is recovered in the lymph nodes to allow NK-cell exit via lymphatics in a CXCR4-independent manner. Therefore, coordinated changes in CXCR4 and S1P5 responsiveness govern NK-cell trafficking.
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.
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.
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 report that ...the metabolic checkpoint kinase mTOR is activated and boosts bioenergetic metabolism upon NK cell exposure to high concentrations of IL-15 whereas low doses of IL-15 only triggers the phosphorylation of the transcription factor STAT5. mTOR stimulates NK cell growth and nutrient uptake and positively feeds back onto the IL-15 receptor. This process is essential to sustain NK cell proliferation during development and acquisition of cytolytic potential upon inflammation or virus infection. The mTORC1 inhibitor rapamycin inhibits NK cell cytotoxicity both in mouse and human, which likely contribute to the immunosuppressant activities of this drug in different clinical settings.
Les cellules natural killer (NK) forment une composante importante de l’immunité innée, dédiée à la défense de l’hôte contre les virus et également impliquée dans l’immunosurveillance des tumeurs. ...Les cellules NK sont distribuées dans tout l’organisme et leur nombre peut augmenter localement au site d’une infection. Elles se développent principalement dans la moelle osseuse et sont perpétuellement renouvelées à partir de ce tissu. Cette revue fait le point sur les facteurs qui régulent l’homéostasie des cellules NK, leur développement, leur différenciation et leur export vers la périphérie. L’accent est mis sur les éléments qui participent à leur homéostasie, en particulier leur renouvellement et leur prolifération. Enfin, nous discutons l’homéostasie des cellules NK dites « mémoire », récemment décrites.
Natural killer (NK) cells are important players of innate immunity, dedicated to the host defense against viruses and also involved in the immune surveillance of tumors. NK cells are widely distributed in the body and their number may increase locally during infection. They develop mainly in the bone marrow and perhaps in other lymphoid organs. They are constantly renewed, with a half-life of about 17 days at the periphery. In this article, we review the factors that regulate the homeostasis of NK cells including their development, differentiation, export to the periphery, their turnover, their homeostatic or antigen-induced proliferation and their survival before or after activation. In addition, we discuss the homeostasis of recently described so-called “memory” NK cells.
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