Mitochondrial Priming by CD28 Klein Geltink, Ramon I; O'Sullivan, David; Corrado, Mauro ...
Cell,
10/2017, Letnik:
171, Številka:
2
Journal Article
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T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We ...show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.
T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are ...independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL‐4 reporter mice in culture and in vivo following exposure to type 2 immunogens. In culture, Il4 alleles had independent, heritable expression probabilities. Modeling showed that in co‐expressors, dual allele transcription occurs for only short periods, limiting per‐cell mRNA variation in individual cells within a population of Th2 cells. In vivo profiles suggested that early in the immune response, IL‐4 output was derived predominantly from single alleles, but co‐expression became more frequent over time and were tuned by STAT6, supporting the probabilistic regulation of Il4 alleles in vivo among committed IL‐4 producers. We suggest an imprinted probability of expression from individual alleles with a short transcriptional shutoff time controls the magnitude of T cell IL‐4 output, but the amount produced per allele is amplified by STAT6 signaling. This form of regulation may be a relevant general mechanism governing cytokine expression.
Kyle et al. demonstrate that Il4 alleles are expressed with independent, heritable expression probabilities in vivo and in vitro but per‐allele amounts are tuned by STAT6 signals. Modeling showed that allele co‐expression was limited in a population of Th2 cells.
Although IL-4 is long associated with CD4 Th2 immune responses, its role in Th2 subset development in non-lymphoid tissues is less clear. We sought to better define IL-4's role in CD4 Th2 responses ...by using transgenic mice that express a dual IL-4 AmCyan/IL-13 DsRed (IL-4AC/IL-13DR) fluorescent reporter on an IL-4-sufficient or IL-4-deficient background. Using primary Th2 immune response models against house dust mite or
(
) allergens, we examined the requirement for IL-4 by each of the defined Th2 subsets in the antigen draining lymph node, skin, and lung tissues. In the lymph node, a CXCR5
PD-1
T follicular helper (Tfh) and a CXCR5
PD-1
Th2 subset could be detected that expressed only IL-4AC but no IL-13DR. The number of IL-4AC
Tfh cells was not affected by IL-4 deficiency whereas the number of IL-4AC
Th2 cells was significantly reduced. In the non-lymphoid dermal or lung tissues of allergen primed or
-infected mice, three strikingly distinct T cell subsets could be detected that were IL-4AC, or IL-4AC/IL-13DR, or IL-13DR CD4. The IL-4- and IL-4/IL-13-expressing subsets were significantly reduced in IL-4-deficient mice, while the numbers of IL-13-expressing CD4 T cells were not affected by IL-4 deficiency indicating that other factors can play a role in directing the development of this Th2 subtype. Taken together, these data indicate that the appearance of IL-4-expressing Tfh cells in the lymph node is not dependent on IL-4 while the appearance of IL-4-expressing Th2 subsets in the lymph node and IL-4, IL-4/IL-13-expressing Th2 subsets in skin and lung tissues of antigen primed mice is significantly IL-4 dependent.
Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate ...disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylphosphatidylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murine lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 924 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. This multi-omic view provides a unique resource and deeper insight into normal pulmonary development.
Sleep quality is an important health-protective factor. Psychosocial factors, including attachment orientation, may be valuable for understanding who is at risk of poor sleep quality and associated ...adverse health outcomes. High attachment anxiety is reliably associated with adverse health outcomes, whereas high attachment avoidance is associated with adverse health outcomes when co-occurring with poor self-regulatory capacity, indexed by heart rate variability (HRV). We examined the associations between attachment anxiety, attachment avoidance, HRV, and sleep quality.
Using longitudinal data from a sample of 171 older adults measured four times over 1 year ( M = 66.18 years old; 67.83% women), we separated the between-person variance (which we call "trait") and within-person variance (which we call "state") for attachment anxiety, attachment avoidance, and HRV (via the root mean square of successive differences). Sleep quality was measured with the Pittsburgh Sleep Quality Index.
Higher trait attachment anxiety was associated with poorer global sleep quality ( B = 0.22, p = .005). Higher state attachment avoidance was associated with poorer sleep quality ( B = -0.13, p = .01), except for those with higher trait HRV. Higher state attachment anxiety was associated with poorer sleep quality ( B = -0.15, p = .002), except for those with higher or mean trait HRV. Higher trait attachment anxiety was associated with poorer sleep quality ( B = -0.31, p = .02), except for those with higher trait HRV.
High trait HRV mitigated the adverse effects of attachment insecurity on sleep quality. Our results suggest that people with high trait HRV had greater self-regulation capacity, which may enable them to enact emotion regulation strategies effectively.
Recent studies have identified a significant warming trend across West Antarctica and the Antarctic Peninsula, which is likely linked to tropical forcing. Here we investigate temporal variations in ...El Niño–Southern Oscillation (ENSO)–related tropical forcing and Southern Annular Mode (SAM)–related forcing on the Amundsen‐Bellingshausen Seas Low and the regional climate during austral spring. We find a spatial dependency regarding the impacts each of these climate modes have on the Antarctic Peninsula: relationships with ENSO and Antarctic Peninsula climate are persistent and significant across the western Peninsula, while relationships with the SAM are persistent and significant across the northeastern Peninsula. Other ENSO/SAM–Peninsula temperature correlations appear weak since 1957 as they vary temporally, fluctuating in response to changing correlations between the SAM index and the Southern Oscillation Index in austral spring. Changes in the ENSO‐SAM correlations are due primarily to the 1988 La Niña/SAM negative event, which significantly altered the location of the ENSO teleconnection in the South Pacific Ocean and, therefore, its influence on the regional climate. Whether or not there is decadal variability in the ENSO‐SAM relationship remains unclear; however, it is evident that the influence across the Peninsula varies in both space and time, related to the strength and spatial extent of the response in the Amundsen‐Bellingshausen Seas. This suggests that in order to accurately attribute the warming to ENSO‐related tropical forcing, it is necessary to consider the role of the regional circulation manifested by the phase of each climate mode together.
Key Points
SAM persistently influences northeast Peninsula climate.
ENSO persistently influences west Peninsula climate.
Time‐varying correlations are related to changes in ENSO‐SAM relationship.
•Inflammatory markers can distinguish bereaved spouses higher on grief severity compared with bereaved spouses with lower grief severity.•Even in a population high on depressive symptoms, there is a ...positive relationship between depression and inflammation.•Similar to the general population, inflammation is an important marker of elevated levels of depression among bereaved spouses.
Grief is conceptualized by strong negative emotions, which include longing, sadness, and preoccupations with thoughts, recollections, and images of the spouse. In the initial months after the loss of a spouse, those who are widowed are at risk for cardiovascular problems and premature mortality. In the general population, depression is characterized by chronic low-grade inflammation, a key predictor of cardiovascular problems, morbidity, and mortality. Although depression and grief share similarities, they are distinct constructs. We aimed to identify if grief was related to inflammation among those who had a spouse recently die. We also sought to determine if those who are widowed and already experience elevated levels of depressive symptoms compared with the general population had higher levels of inflammation compared with those who are widowed who report fewer depressive symptoms. Ninety-nine recently bereaved individuals (M = 84.74 days since passing, SD = 18.17) completed a blood draw and psychological assessments. Proinflammatory T cell-derived cytokines were assessed, which included interferon gamma (IFN-γ), interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL17-A, and IL-2. Bereaved individuals with a higher grief severity (using an established cut-score) had higher levels of the proinflammatory cytokines IFN-γ, IL-6, and TNF-α than those with less grief severity. Those who experienced higher levels of depression exhibited elevated levels of proinflammatory cytokines compared with those who had lower levels of depression (using a continuous measure of depressive symptoms, as well as an established cut score). This is the first study to demonstrate that inflammatory markers can distinguish those who are widowed based on grief severity such that those who are higher on grief severity have higher levels of inflammation compared with those who are lower on grief severity. These findings also add to the broader literature on depression and inflammation by showing that even in a population with high levels of depressive symptoms, there is a positive relationship between depression and inflammation.
Losing a spouse is a distressing life event that can negatively affect both mental and physical health. Stress-induced health consequences often include increased risk of cardiovascular disease and ...altered immune system functioning marked by increased inflammation. Here, we sought to identify individual difference factors that covary with problematic inflammatory outcomes.
We measured recently bereaved spouses' (n = 99) propensity to use emotion regulation strategies and peripheral inflammation, as measured by levels of proinflammatory cytokines after ex vivo stimulation of peripheral leukocytes with T-cell agonists. Specifically, we measured participants' use of cognitive reappraisal, an adaptive emotion regulation strategy in many contexts, and expressive suppression, a less adaptive emotion regulation strategy that involves actively inhibiting emotions after already experiencing them.
Bereaved spouses who self-reported frequently using expressive suppression as an emotion regulation strategy tended to have a more pronounced inflammatory response, as indexed by higher levels of a composite cytokine index consisting of interleukin (IL) 17A, IL-2, IL-6, tumor necrosis factor α, and interferon-γ (b = 0.042), as well as tumor necrosis factor α (b = 0.083) and interferon-γ (b = 0.098) when analyzed individually. Notably, these associations were observed in both unadjusted and adjusted models, with the latter including known covariates of inflammation and other potential confounding variables.
These findings suggest that bereaved spouses' use of emotion regulation strategies is associated with altered immune functioning, and such a link may be an important biological pathway by which interventions targeting affect may improve immune system-related health outcomes.
Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show ...that in activated CD8
T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8
T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
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