Regulatory T cells (T reg cells), a distinct subset of CD4 + T cells, are necessary for the maintenance of immune self-tolerance and homeostasis 1 , 2 . Recent studies have demonstrated that T reg cells exhibit a unique metabolic profile characterized by an increase in mitochondrial metabolism relative to other CD4 + effector subsets 3 , 4 . Furthermore, the T reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration 5 , 6 ; however, it remains unknown whether the mitochondrial respiratory chain is required for T reg cell suppressive capacity, stability, and survival. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting T reg cell number. Mice lacking mitochondrial complex III specifically in T reg cells displayed a loss of T reg cell suppressive capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III had decreased expression of genes associated with T reg function while maintaining stable Foxp3 expression. Loss of complex III in T reg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases 7 . Thus, T reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.

Psychostimulant-induced alteration of dendritic spines on dopaminoceptive neurons in nucleus accumbens (NAcc) has been hypothesized as an adaptive neuronal response that is linked to longlasting addictive behaviors. NAcc is largely composed of two distinct subpopulations of medium-sized spiny neurons expressing high levels of either dopamine D1 or D2 receptors. In the present study, we analyzed dendritic spine density after chronic cocaine treatment in distinct D1 or D2 receptor-containing medium-sized spiny neurons in NAcc. These studies made use of transgenic mice that expressed EGFP under the control of either the D1 or D2 receptor promoter (Drd1-EGFP or Drd2-EGFP). After 28 days of cocaine treatment and 2 days of withdrawal, spine density increased in both Drd1-EGFP-and Drd2-EGFP-positive neurons. However, the increase in spine density was maintained only in Drd1-EGFP-positive neurons 30 days after drug withdrawal. Notably, increased ⌬FosB expression also was observed in Drd1-EGFP-and Drd2-EGFP-positive neurons after 2 days of drug withdrawal but only in Drd1-EGFP-positive neurons after 30 days of drug withdrawal. These results suggest that the increased spine density observed after chronic cocaine treatment is stable only in D1-receptor-containing neurons and that ⌬FosB expression is associated with the formation and͞or the maintenance of dendritic spines in D1 as well as D2 receptor-containing neurons in NAcc.T he mesolimbic dopaminergic pathway is composed of neurons in the ventral tegmental area that innervate the nucleus accumbens (NAcc), olfactory tubercle, prefrontal cortex, and amygdala (1), whereas nigrostriatal dopaminergic neurons in the substantia nigra (pars compacta) provide an ascending projection to dorsal striatum (2). Psychostimulants elevate synaptic concentrations of dopamine in NAcc: cocaine, by blocking dopamine uptake from the synaptic cleft, and amphetamine, by promoting dopamine release from nerve terminals (3-5). Repeated, intermittent administration of psychostimulants results in augmented behavioral responses (sensitization) to the acute stimulatory effects of these drugs (6-8). Most lines of evidence suggest that adaptive changes in the ventral tegmental areaNAcc dopaminergic system are central to alterations in the experience-dependent plasticity that underlies drug-induced behavior.In addition to dopamine, glutamate is required for the development of behavioral sensitization in response to psychostimulants (9, 10). Medium-sized spiny neurons (MSNs) in ventral striatum receive excitatory glutamatergic projections from prefrontal cortex that synapse onto the heads of dendritic spines. MSNs also are the major target for dopaminergic axons that synapse onto spine necks (1,11,12). Therefore, dendritic spines in MSNs represent the cellular compartment where dopaminergic and glutamatergic transmission are initially integrated. Dopamine acts on two major receptor subfamilies, the D1 subfamily (D1 and D5 subtypes) and the D2 subfamily (D2, D3, and D4 subtypes) (13). In dorsal striatum, ...

Dystrophic neurites are associated with fibrillar amyloid deposition in Alzheimer's disease (AD), but the frequency and types of changes in synaptic structures near amyloid deposits have not been well characterized. Using high-resolution confocal microscopy to image lipophilic dye-labeled dendrites and thioflavin-S-labeled amyloid plaques, we systematically analyzed the structural changes of dendrites associated with amyloid deposition in both a transgenic mouse model of AD (PSAPP) and in human postmortem brain. We found that in PSAPP mice, dendritic branches passing through or within 40 mum from amyloid deposits displayed various dendritic abnormalities such as loss of dendritic spines, shaft atrophy, bending, abrupt branch endings, varicosity formation, and sprouting. Similar structural alterations of dendrites were seen in postmortem human AD tissue, with spine loss as the most common abnormality in both PSAPP mice and human AD brains. These results demonstrate that fibrillar amyloid deposits and their surrounding microenvironment are toxic to dendrites and likely contribute to significant disruption of neuronal circuits in AD.

Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67’s interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As CATACOMB expression is regulated through DNA methylation/demethylation, we propose CATACOMB as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.