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.
Mutually exclusive expression of T-bet and Eomes drives the development of distinct NK cell lineages with complementary functions.
The transcription factor Zeb2 cooperates with T-bet to control NK cell maturation, viability, and exit from the bone marrow and is essential for rejection of melanoma lung metastasis.
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. (Blood. 2011;118(18):4863-4871) IntroductionNatural killer (NK) cells are lymphocytes of the innate immune system that are involved in the early control of infections by viruses and intracellular bacteria or parasites. 1 They can kill cells recognized as targets through a battery of surface receptors 2 and also produce large amounts of cytokines such as IFN-␥ upon activation. 1 Several NK-cell subsets have been described on the basis of surface expression of the TNF superfamily member CD27 and the integrin CD11b: CD11b low CD27 low (thereafter called double negative or "DN"), CD11b low CD27 high NK cells ("CD11b low "), CD11b high CD27 high (double positive or "DP"), and CD11b high CD27 low ("CD27 low "). 3,4 We previously found that NK-cell maturation is a 4-stage process that starts at the DN stage and follows the pathway DN 3 CD11b low 3 DP 3 CD27 low . 3 DN NK cells are very rare and immature and could arguably correspond to precursors. All 3 other subsets are quite abundant in lymphoid organs, but their distribution is very different: CD11b low NK cells are mostly located within the BM and lymph nodes (LNs); CD27 low NK cells are mostly found in the blood, the spleen, and nonlymphoid organs such as liver and lung; and DP NK cells are more evenly distributed in these organs. 5 NK cells develop mainly in the BM. Like other lymphocytes, they are thought to reach the blood circulation via venous sinusoids. 6 Once in the periphery, they can also enter the LNs through a CD62L-dependent process. 7 Exit from the LNs presumably occurs via medullar sinusoids that connect to efferent lymphatics. 6 The chemotactic receptors that control the differential distribution of NK-cell subsets a...
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.
The 101-residue long Tat protein of primary isolate 133 of the human immunodeficiency virus type 1 (HIV-1), wt-Tat(133) displays a high transactivation activity in vitro, whereas the mutant thereof, STLA-Tat(133), a vaccine candidate for HIV-1, has none. These two proteins were chemically synthesized and their biological activity was validated. Their structural properties were characterized using circular dichroism (CD), fluorescence emission, gel filtration, dynamic light scattering, and small angle X-ray scattering (SAXS) techniques. SAXS studies revealed that both proteins were extended and belong to the family of intrinsically unstructured proteins. CD measurements showed that wt-Tat(133) or STLA-Tat(133) underwent limited structural rearrangements when complexed with specific fragments of antibodies. Crystallization trials have been performed on the two forms, assuming that the Tat(133) proteins might have a better propensity to fold in supersaturated conditions, and small crystals have been obtained. These results suggest that biologically active Tat protein is natively unfolded and requires only a limited gain of structure for its function.
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