Human Cytokine-Induced Memory-Like Natural Killer Cells

Natural killer (NK) cells are innate lymphoid cells that are important for host defense against infection and mediate antitumor responses. Recent reports from several laboratories have identified that NK cells can remember a prior activation event and consequently respond more robustly when restimulated, a property termed innate NK cell memory. NK cell memory has now been identified following hapten exposure, viral infection, and combined cytokine preactivation with IL-12, IL-15, and IL-18. Many questions in the field remain regarding the cellular and molecular mechanisms regulating memory NK cells and their responses, as well as their formation and function in mice and humans. Here we review our current understanding of cytokine-induced memory-like (CIML) NK cells that are generated by combined preactivation with IL-12, IL-15, and IL-18. These cells exhibit enhanced NK cell effector functions weeks after the initial cytokine preactivation. Further, we highlight the preclinical rationale and ongoing therapeutic application of CIML NK cells for adoptive immunotherapy in patients with hematologic malignancies.

Mechanism of Action of a Distal NF-κB-Dependent Enhancer

ABSTRACT The monocyte chemoattractant protein 1 gene (MCP-1) is regulated by TNF through an NF-κB-dependent distal enhancer and an Sp1-dependent promoter-proximal regulatory region. In the silent state, only the distal regulatory region is accessible to transcription factors. Upon activation by tumor necrosis factor, NF-κB binds to the distal regulatory region and recruits CBP and p300. CBP and p300 recruitment led to specific histone modifications that ultimately enabled the binding of Sp1 to the proximal regulatory region. During this process, a direct interaction between the distal and proximal regulatory regions occurred. Sp1, NF-κB, CBP, and p300 were required for this interaction. CBP/p300-mediated histone modifications enhanced the binding of the coactivator CARM1 to the distal regulatory region. CARM1, which is necessary for MCP-1 expression, was not required for distal-proximal region interactions, suggesting that it plays a later downstream activation event. The results describe a model in which the separation of the distal enhancer from the promoter-proximal region allows for two independent chromatin states to exist, preventing inappropriate gene activation at the promoter while at the same time allowing rapid induction through the distal regulatory region.

Caspase activation

Caspase activation is the 'point of no return' commitment to cell death. Synthesized as inactive zymogens, it is essential that the caspases remain inactive until the death signal is received. It is known for the downstream executioner caspases-3 and -7 that the activation event is proteolytic cleavage, and this had been assumed to apply to the initiator caspases as well. However, recent studies conducted on caspases-2, -8 and -9 have challenged this tenet of caspase activation. In this review we focus on the molecular details of caspase activation, with emphasis on recent work that provides a pleasing explanation for the differential requirements for the activation of executioner and initiator caspases.

BROWNIAN MOTION IN A TWO-DIMENSIONAL POTENTIAL: A NEW NUMERICAL SOLUTION METHOD

Studying the Brownian motion of a particle in a two-dimensional potential with two saddle-point passages connecting two wells, we compute the activation rate of the particle from one well into the other and illustrate a new technique for obtaining numerical solution to the Langevin equation for transition probability. By virtue of a Langevin equation with negative friction, this new method directly traces the active part of an activation event, without having to simulate the long period of small fluctuations in a well between two successful events, and computes the statistical weight for each successful activation. It makes feasible for us to numerically integrate the Langevin equation for transition probability even when the activation energy barrier (i.e. the potential difference between the saddle point and the well) is much greater than thermal energy k B T where other methods fail to be tractable.

Modeling of Dislocation Mobility in Metals: Effect of Obstacles and Thermal Processes

ABSTRACTThermally activated dislocation glide velocity through weak point obstacle arrays is studied analytically and computationally. Thermal activation rate is estimated using the modified Friedel relations under the weak obstacle approximation. The average flight velocity after an activation event as a function of stress and temperature is obtained by the discrete dislocation dynamics (DD). This numerical calculation includes the effect of self-stress, interaction with electrons and phonons, and the inertial effect. These results are implemented into a phenomenological model to study the dislocation velocity under various conditions. The model can reproduce both obstacle control and drag control motion in low and high velocity regions, and a flow stress anomaly at transient regions.

Rapid G protein-regulated activation event involved in lymphocyte binding to high endothelial venules.

The homing of blood borne lymphocytes into lymph nodes and Peyer's patches is mediated in part by recognition and binding to specialized high endothelial venules (HEV). Here we demonstrate that a rapid pertussis toxin-sensitive lymphocyte activation event can participate in lymphocyte recognition of HEV. In situ video microscopic analyses of lymphocyte interactions with HEV in exteriorized mouse Peyer's patches reveal that pertussis toxin has no effect on an initial "rolling" displayed by many lymphocytes, but inhibits an activation-dependent "sticking" event required for lymphocyte arrest. This is the first demonstration that physiologic lymphocyte-endothelial interactions can involve sequential rolling, activation, and activation-dependent arrest, previously shown only for neutrophils. The inhibitory effect of the toxin is dependent on its G protein-modifying ADP-ribosyltransferase activity and can be reversed by phorbol myristic acetate, which bypasses cell surface receptors to trigger activation-dependent adhesion. Lymphocyte sticking can occur within 1-3 s after initiation of rolling. We conclude that a rapid receptor-mediated activation event involving G protein signaling can trigger stable lymphocyte attachment to HEV in vivo, and may play a critical role in regulating lymphocyte homing.