CD4 T cell-dependent antibody responses are essential for limiting Plasmodium parasite replication and the severity of malaria; however, the factors that regulate humoral immunity during highly ...inflammatory, Th1-biased systemic infections are poorly understood. Using genetic and biochemical approaches, we show that Plasmodium infection-induced type I interferons limit T follicular helper accumulation and constrain anti-malarial humoral immunity. Mechanistically we show that CD4 T cell-intrinsic type I interferon signaling induces T-bet and Blimp-1 expression, thereby promoting T regulatory 1 responses. We further show that the secreted effector cytokines of T regulatory 1 cells, IL-10 and IFN-γ, collaborate to restrict T follicular helper accumulation, limit parasite-specific antibody responses, and diminish parasite control. This circuit of interferon-mediated Blimp-1 induction is also operational during chronic virus infection and can occur independently of IL-2 signaling. Thus, type I interferon-mediated induction of Blimp-1 and subsequent expansion of T regulatory 1 cells represent generalizable features of systemic, inflammatory Th1-biased viral and parasitic infections that are associated with suppression of humoral immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IL-10 is a pleiotropic cytokine expressed during malaria, a disease characterized by short-lived, parasite-specific Ab responses. The role of IL-10 in regulating B cell responses during malaria is ...not known. In this study we report that IL-10 is essential for anti-Plasmodium humoral immunity. We identify that germinal center (GC) B cell reactions, isotype-switched Ab responses, parasite control, and host survival require B cell-intrinsic IL-10 signaling. IL-10 also indirectly supports humoral immunity by suppressing excessive IFN-γ, which induces T-bet expression in B cells. Genetic ablation of either IFN-γ signaling or T-bet expression in B cells substantially enhanced GC B cell responses and anti-Plasmodium Ab production. Together, our data show that B cell-intrinsic IL-10 enhances whereas B cell-intrinsic IFN-γ and T-bet suppress GC B cell responses and anti-Plasmodium humoral immunity. These data identify critical immunoregulatory circuits in B cells that may be targeted to promote long-lived humoral immunity and resistance to malaria.
Influenza A virus (IAV) is a widespread infectious agent commonly found in mammalian and avian species. In humans, IAV is a respiratory pathogen that causes seasonal infections associated with ...significant morbidity in young and elderly populations, and has a large economic impact. Moreover, IAV has the potential to cause both zoonotic spillover infection and global pandemics, which have significantly greater morbidity and mortality across all ages. The pathology associated with these pandemic and spillover infections appear to be the result of an excessive inflammatory response leading to severe lung damage, which likely predisposes the lungs for secondary bacterial infections. The lung is protected from pathogens by alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The importance of mast cells during bacterial and parasitic infections has been extensively studied; yet, the role of these hematopoietic cells during viral infections is only beginning to emerge. Recently, it has been shown that mast cells can be directly activated in response to IAV, releasing mediators such histamine, proteases, leukotrienes, inflammatory cytokines, and antiviral chemokines, which participate in the excessive inflammatory and pathological response observed during IAV infections. In this review, we will examine the relationship between mast cells and IAV, and discuss the role of mast cells as a potential drug target during highly pathological IAV infections. Finally, we proposed an emerging role for mast cells in other viral infections associated with significant host pathology.
The latent HIV reservoir is generated following HIV infection of activated effector CD4 T cells, which then transition to a memory phenotype. Here, we describe an
method, called QUECEL (
iescent
...ffector
ll
atency), that mimics this process efficiently and allows production of large numbers of latently infected CD4
T cells. Naïve CD4
T cells were polarized into the four major T cell subsets (Th1, Th2, Th17, and Treg) and subsequently infected with a single-round reporter virus which expressed GFP/CD8a. The infected cells were purified and coerced into quiescence using a defined cocktail of cytokines, including tumor growth factor beta, interleukin-10 (IL-10), and IL-8, producing a homogeneous population of latently infected cells. Flow cytometry and transcriptome sequencing (RNA-Seq) demonstrated that the cells maintained the correct polarization phenotypes and had withdrawn from the cell cycle. Key pathways and gene sets enriched during transition from quiescence to reactivation include E2F targets, G
M checkpoint, estrogen response late gene expression, and c-myc targets. Reactivation of HIV by latency-reversing agents (LRAs) closely mimics RNA induction profiles seen in cells from well-suppressed HIV patient samples using the envelope detection of
transcription sequencing (EDITS) assay. Since homogeneous populations of latently infected cells can be recovered, the QUECEL model has an excellent signal-to-noise ratio and has been extremely consistent and reproducible in numerous experiments performed during the last 4 years. The ease, efficiency, and accuracy of the mimicking of physiological conditions make the QUECEL model a robust and reproducible tool to study the molecular mechanisms underlying HIV latency.
Current primary cell models for HIV latency correlate poorly with the reactivation behavior of patient cells. We have developed a new model, called QUECEL, which generates a large and homogenous population of latently infected CD4
memory cells. By purifying HIV-infected cells and inducing cell quiescence with a defined cocktail of cytokines, we have eliminated the largest problems with previous primary cell models of HIV latency: variable infection levels, ill-defined polarization states, and inefficient shutdown of cellular transcription. Latency reversal in the QUECEL model by a wide range of agents correlates strongly with RNA induction in patient samples. This scalable and highly reproducible model of HIV latency will permit detailed analysis of cellular mechanisms controlling HIV latency and reactivation.
Influenza A virus (IAV) is a major respiratory pathogen of both humans and animals. The lung is protected from pathogens by alveolar epithelial cells, tissue-resident alveolar macrophages, dendritic ...cells, and mast cells. The role of alveolar epithelial cells, endothelial cells, and alveolar macrophages during IAV infection has been studied previously. In this study, we address the role of mast cells during IAV infection. Respiratory infection with A/WSN/33 causes significant disease and immunopathology in C57BL/6 mice but not in B6.Cg-Kit(W-sh) mice, which lack mast cells. During in vitro coculture, A/WSN/33 caused mast cells to release histamine, secrete cytokines and chemokines, and produce leukotrienes. Moreover, when mast cells were infected with IAV, the virus did not replicate within mast cells. Importantly, human H1N1, H3N2, and influenza B virus isolates also could activate mast cells in vitro. Mast cell production of cytokines and chemokines occurs in a RIG-I/MAVS-dependent mechanism; in contrast, histamine production occurred through a RIG-I/MAVS-independent mechanism. Our data highlight that, following IAV infection, the response of mast cells is controlled by multiple receptors. In conclusion, we identified a unique inflammatory cascade activated during IAV infection that could potentially be targeted to limit morbidity following IAV infection.
The purpose of this study was to examine the associations among race and socioeconomic factors (receiving social security disability, insurance type, and income) with undergoing bariatric surgery and ...weight loss outcomes in a racially diverse, urban cohort of bariatric surgery candidates (
N
= 314). Patients with private insurance and who identified as Caucasian were more likely to undergo bariatric surgery. Income significantly predicted percentage of excess weight loss 1 year after surgery, although this was no longer significant when accounting for race. Race and socioeconomic factors should be considered during psychosocial evaluations to support patients at risk of surgical attrition and poorer weight loss outcomes. Future research should explore policy solutions to improve access, while qualitative work may help with understanding racial disparities in bariatric surgery.
We show here how differences in surface composition for monolayer (ML)-tethered pyridine (Py)-treated CdSe quantum dots (QDs) affect band edge energetics, as a function of QD diameter. We compare ...UV–vis spectroscopy of QD solutions and X-ray (XPS) and ultraviolet (UPS) photoelectron spectroscopy of QDs tethered to 1,6-hexanedithiol-modified Au surfaces. Differences in QD surface composition are brought about by differences in solvent composition during displacement of the native, X-type octadecylphosphonate (ODP–) ligands with Py and by differences in exposure to trace H2O and O2 during QD processing. Prior to surface tethering, exchange of the ODP– ligands with Py ligands under ambient (A) conditions leads to some surface passivation of the QD and no appreciable reduction in the spectroscopically estimated QD diameter. QDs processed in completely inert (I) environments (O2 and H2O below detection limits in the solvents, processing environments, and during analysis) undergo a small decrease in diameter during Py exchange and an increase in size dispersity. These simple differences in processing conditions lead to important differences in QD band edge energetics which will impact their use as photocatalysts and photovoltaic or light-emitting diode active layers. XPS characterization of Py-capped QD-tethered MLs, compared with freshly etched CdSe(0001) single-crystal surfaces, indicates that I QDs show a higher Se surface coverage relative to A QDs. For A QDs, we propose that trace H2O present during processing provides a proton source that facilitates ODP– desorption and replacement with charge-compensating HO– ligands, which inhibits subsequent changes in QD surface composition. UPS-derived size-quantized ionization potentials (IPs) and electron affinities (EAs) for I QDs, corrected for shifts in the local vacuum level, closely track the energetic shifts predicted by the effective mass approximation (EMA). The vacuum level-corrected IP/EA values for A QDs show sizeable deviations from the EMA. We also describe an approach for characterization of UPS data for these QD MLs, which greatly enhances the sensitivity to mid-gap states above the VBM (seen for I QDs which are slightly enriched in surface Se) and offers a general approach to all semiconductor materials with low density of states in the valence band region. This study confirms the influence of ligand modification and processing environment on QD surface composition, which in turn impacts the CdSe QD energy levels that are important to applications in photocatalysis and optoelectronic device platforms.
Undergraduate women are at high risk of experiencing sexual assault during their college years. Research has established a strong link between sexual victimization and psychological distress. ...Although the relationship between sexual victimization and distress has been established, little is known about how the use of university-affiliated sexual assault resources influences mental health outcomes for survivors. The aims of this cross-sectional study were to describe the characteristics of women who used campus survivor resources following a sexual assault during college, examine correlates of campus resource use, and examine correlates and predictors of mental health of women who have been sexually assaulted during college. An online anonymous survey was sent to undergraduate women at two public universities in a mid-Atlantic state. Participants were female, undergraduate students (N = 362) who had been sexually assaulted during their time at college. Few women (n = 98, 27.1%) used campus resources following a sexual assault. We found significant relationships between participants’ use of campus survivor resources and experiencing a sexual assault prior to entering college, experiencing more severe sexual assaults, acknowledging the assault as a rape, feeling more self-blame, and experiencing more psychological distress. Campus resource use was significantly associated with poorer mental health outcomes. The cross-sectional nature of this study limited our ability to explore the reason for this. Further research is needed to explore the role campus resources play in supporting survivors during the recovery process. Given the high rate of sexual assaults on college campuses and the known negative psychological impact of sexual assault, it is imperative that campuses offer resources that are effective in meeting the needs of survivors.
The role of the negative elongation factor (NELF) in maintaining HIV latency was investigated following small hairpin RNA (shRNA) knockdown of the NELF-E subunit, a condition that induced high levels ...of proviral transcription in latently infected Jurkat T cells. Chromatin immunoprecipitation (ChIP) assays showed that latent proviruses accumulate RNA polymerase II (RNAP II) on the 5′ long terminal repeat (LTR) but not on the 3′ LTR. NELF colocalizes with RNAP II, and its level increases following proviral induction. RNAP II pause sites on the HIV provirus were mapped to high resolution by ChIP with high-throughput sequencing (ChIP-Seq). Like cellular promoters, RNAP II accumulates at around position +30, but HIV also shows additional pausing at +90, which is immediately downstream of a transactivation response (TAR) element and other distal sites on the HIV LTR. Following NELF-E knockdown or tumor necrosis factor alpha (TNF-α) stimulation, promoter-proximal RNAP II levels increase up to 3-fold, and there is a dramatic increase in RNAP II levels within the HIV genome. These data support a kinetic model for proviral transcription based on continuous replacement of paused RNAP II during both latency and productive transcription. In contrast to most cellular genes, HIV is highly activated by the combined effects of NELF-E depletion and activation of initiation by TNF-α, suggesting that opportunities exist to selectively activate latent HIV proviruses.
Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for ...resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure.
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•Reagents generated to study Plasmodium-specific memory CD4 T cell development•Th1- and Tfh-like memory CD4 T cells exhibit functional overlap during recall•Potent B cell helper function can be recalled from Th1-like memory cells•Functions of parasite-specific memory CD4 T cells are enhanced by ligation of OX40
Th1 CD4 T cells are widely described as terminally differentiated with a relatively reduced capacity to form memory or support humoral immunity. Using experimental malaria models, Zander et al. show that potent proliferative and B cell helper activity unexpectedly resides within the Plasmodium-specific Th1-like memory CD4 T cell compartment.
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