Highlights d A single-cell atlas of BM ILCs and lung ILCs of healthy, infected, and parabiotic mice d Identification of tissue-associated ILC progenitors in neonatal and adult lung d Cells recruited from BM generate the entire spectrum of ILC2s in infected lungs d Local cues imprint the phenotypes of ILC2s differentiating in the adult lung

The neurons of many basal ganglia nuclei, including the external and internal globus pallidus (GPe and GPi, respectively) and the substantia nigra pars reticulata (SNr) are characterized by their high-frequency (50 -100 spikes/s) tonic discharge (HFD). However, the high firing rate of GPe neurons is interrupted by long pauses. We studied the extracellularly recorded spiking activity of 212 well-isolated HFD GPe and 52 GPi/SNr neurons from five monkeys during different states of behavioral activity. An algorithm that maximizes the surprise function was used to detect pauses and pauser cells ("pausers"). Only 6% of the GPi/SNr neurons versus as many as 56% of the GPe neurons were classified as pausers. The GPe average pause duration equals 0.62 s. The interpause intervals follow a Poissonian distribution with a frequency of 13 pauses/minute. No linear relationship was found between pause parameters (duration or frequency) and the firing rate of the cell. Pauses were preceded by various changes in firing rate but not dominantly by a decrease. The average amplitude and duration of the spike waveform was modulated only after the pause but not before it. Pauses of pairs of cells that were recorded simultaneously were not correlated. The probability of GPe cells to pause spontaneously was extremely variable among monkeys (30 -90%) and inversely related to the degree of the monkey's motor activity. These findings suggest that spontaneous GPe pauses are related to low-arousal periods and are generated by a process that is independent of the discharge properties of the cells.

High-frequency stimulation of the globus pallidus (GP) has emerged as a successful tool for treating Parkinson's disease and other motor disorders. However, the mechanism governing its therapeutic effect is still under debate. To shed light on the basic mechanism of deep brain stimulation (DBS), we performed microstimulation in the GP of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey while recording with other microelectrodes in the same nucleus. We used robust methods to reduce the stimulus artifact, and 600 -3000 repetitions of a single stimulus and of high-frequency short trains (10 -40 stimuli), enabling high temporal resolution analysis of neural responses. Low-frequency stimulation yielded a typical three-stage response: short-term (2-3 msec duration) activity, followed by mid-term (15-25 msec) inhibition, and occasionally longer-term (30 -40 msec) excitation. Trains of high-frequency stimuli elicited complex locking of the response to the stimuli in most neurons. The locking displayed a stereotypic temporal structure consisting of three short-duration (1-2 msec) phases: an initial (mean latency ϭ 2.9 msec) excitation followed by an inhibition (4.6 msec) and a second excitation (6.3 msec). The change in the mean firing rate was mixed; the majority of the neurons displayed partial inhibition during the stimulus train. Slow inhibitory and excitatory multiphase changes in the firing rate were observed after the stimulus trains. The activity of neurons recorded simultaneously displayed rate correlations but no spike-to-spike correlations. Our results suggest that the effect of DBS on the GP is not complete inhibition but rather a complex reshaping of the temporal structure of the neuronal activity within that nucleus.

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CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2;Flt3 AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.

Key Points• PML-RARA and AML1-ETO evade NK cell recognition by specifically downregulating the expression of CD48.• The findings are relevant to AML patients bearing these specific translocations.PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immuoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48. (Blood. 2014;123(10):1535-1543 Introduction Acute myeloid leukemia (AML) is the most common acute leukemia in adults. 1 There are several types of AML (approximately 30%) that are characterized by chromosomal translocations, which generate oncogenic fusion proteins.2 Two of the most common translocations in AML are t(15:17), which gives rise to the fusion protein PML-RARA, and t(8:21), which generates the fusion protein RUNX1-RUNX1T1 (AML1-ETO).3,4 Although these fusion proteins were discovered more than 20 years ago, 5,6 it is not known whether they provide immune evasion properties to AML tumors.Over the past few decades it has been established that natural killer (NK) cells, which are part of the innate immune system, play an important role in killing cancerous cells, 7,8 and specifically AML cells. 9,10 Several studies have found that AML patients who received transplants from NK alloreactive donors had lower relapse rates and improved disease-free survival. [11][12][13] Furthermore, it was recently reported that the presence of the NK cell receptor KIR2DS1, in matched unrelated donors, is associated with distinct outcomes of allogeneic hematopoietic stem cell transplantation in AML patients. 14 Finally, it was shown in several studies that NK cell activity correlates with clinical parameters of AML patients. 15,16 Killing by NK cells is mediated by several killer receptors that recognize distinct ligands. [17][18][19][20][21][22][23][24] Several human killer receptors, such as NKp44 and NKp30, have no mouse orthologs, and others, such as 2B4, have a mouse ortholog protein with opposing functions. In humans, 2B4 functions as an activating receptor, [25][26][27] whereas in mice, it mainly functions as an inhibitory receptor. 28,29 However, in both cases it recognizes CD48. [25][26][27][28] Despite the crucial role played by NK cells in eliminating AML tumors, the NK cell recognition of AML tumor cells is impaired at several levels (r...

Regulatory T cells (Treg cells) represent a CD4 + T-cell lineage that plays a critical role in restraining immune responses to self and foreign antigens and associated inflammation. Due to the suppressive function of Treg cells, inhibition or ablation of these cells can be used to boost the immunity against malignant cells. On the other hand, augmenting the activity of Treg cells can be employed for the treatment of inflammatory or autoimmune diseases and allogeneic conflicts associated with transplantation. Graft-versus-host disease (GvHD) is a leading cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT). In this review, we describe basic biological properties of Treg cells and their role in GvHD. We focus on the application of adoptive transfer of Treg cells and the therapeutic modulation of their activity for the prevention and treatment of GvHD in pre-clinical models and in clinical settings. We also discuss the main obstacles to applying Treg cell-based therapies for GvHD in clinical practice.