Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis

Background Multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), is characterized by blood-brain barrier (BBB) disruption and massive infiltration of activated immune cells. Engagement of programmed cell death-1 (PD-1) expressed on activated T cells with its ligands (PD-L1 and PD-L2) suppresses T cell responses. We recently demonstrated in MS lesions elevated PD-L1 expression by glial cells and absence of PD-1 on many infiltrating CD8 T cells. We have now investigated whether human brain endothelial cells (HBECs), which maintain the BBB, can express PD-L1 or PD-L2 and thereby modulate T cells. Methods We used primary cultures of HBECs isolated from non-tumoral CNS tissue either under basal or inflamed conditions. We assessed the expression of PD-L1 and PD-L2 using qPCR and flow cytometry. Human CD8 T cells were isolated from peripheral blood of healthy donors and co-cultured with HBECs. Following co-culture with HBECs, proliferation and cytokine production by human CD8 T cells were measured by flow cytometry whereas transmigration was determined using a well established in vitro model of the BBB. The functional impact of PD-L1 and PD-L2 provided by HBECs was determined using blocking antibodies. We performed immunohistochemistry for the detection of PD-L1 or PD-L2 concurrently with caveolin-1 (a cell specific marker for endothelial cells) on post-mortem human brain tissues obtained from MS patients and normal controls. Results Under basal culture conditions, PD-L2 is expressed on HBECs, whilst PD-L1 is not detected. Both ligands are up-regulated under inflammatory conditions. Blocking PD-L1 and PD-L2 leads to increased transmigration and enhanced responses by human CD8 T cells in co-culture assays. Similarly, PD-L1 and PD-L2 blockade significantly increases CD4 T cell transmigration. Brain endothelium in normal tissues and MS lesions does not express detectable PD-L1; in contrast, all blood vessels in normal brain tissues are PD-L2-positive, while only about 50% express PD-L2 in MS lesions. Conclusions Our observations suggest that brain endothelial cells contribute to control T cell transmigration into the CNS and immune responses via PD-L2 expression. However, such impact is impaired in MS lesions due to downregulation of endothelium PD-L2 levels

Effects of cardiotrophin on adipocytes

Cardiotrophin (CT-1) is a naturally occurring protein member of the interleukin (IL)-6 cytokine family and signals through the gp130/leukemia inhibitory factor receptor (LIFR) heterodimer. The formation of gp130/ LIFR complex triggers the auto/trans-phosphorylation of associated Janus kinases, leading to the activation of Janus kinase/STAT and MAPK (ERK1 and -2) signaling pathways. Since adipocytes express both gp130 and LIFR proteins and are responsive to other IL-6 family cytokines, we examined the effects of CT-1 on 3T3-L1 adipocytes. Our studies have shown that CT-1 administration results in a dose- and time-dependent activation and nuclear translocation of STAT1, -3, -5A, and -5B as well as ERK1 and -2. We also confirmed the ability of CT-1 to induce signaling in fat cells in vivo. Our studies revealed that neither CT-1 nor ciliary neurotrophic factor treatment affected adipocyte differentiation. However, acute CT-1 treatment caused an increase in SOCS-3 mRNA in adipocytes and a transient decrease in peroxisome proliferator-activated receptor γ (PPARγ) mRNA that was regulated by the binding of STAT1 to the PPARγ2 promoter. The effects of CT-1 on SOCS-3 and PPARγ mRNA were independent of MAPK activation. Chronic administration of CT-1 to 3T3-L1 adipocytes resulted in a decrease of both fatty acid synthase and insulin receptor substrate-1 protein expression yet did not effect the expression of a variety of other adipocyte proteins. Moreover, chronic CT-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin-stimulated glucose uptake. In summary, CT-1 is a potent regulator of signaling in adipocytes in vitro and in vivo, and our current efforts are focused on determining the role of this cardioprotective cytokine on adipocyte physiology

Cross-talk among gp130 cytokines in adipocytes

The interleukin-6 (IL-6) family of cytokines is a family of structurally and functionally related proteins, including IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). These proteins are also known as gp130 cytokines because they all share gp130 as a common transducer protein within their functional receptor complexes. Several of these cytokines (LIF, OSM, CNTF, and CT-1) also utilize the LIF receptor (LIFR) as a component of their receptor complex. We have shown that all of these cytokines are capable of activating both the JAK/STAT and p42/44 mitogen-activated protein kinase signaling pathways in 3T3-L1 adipocytes. By performing a variety of preincubation studies and examining the ability of these cytokines to activate STATs, ERKs, and induce transcription of SOCS-3 mRNA, we have also examined the ability of gp130 cytokines to modulate the action of their family members. Our results indicate that a subset of gp130 cytokines, in particular CT-1, LIF, and OSM, has the ability to impair subsequent signaling activity initiated by gp130 cytokines. However, IL-6 and CNTF do not exhibit this cross-talk ability. Moreover, our results indicate that the cross-talk among gp130 cytokines is mediated by the ability of these cytokines to induce ligand-dependent degradation of the LIFR, in a proteasome-independent manner, which coincides with decreased levels of LIFR at the plasma membrane. In summary, our results demonstrate that an inhibitory cross-talk among specific gp130 cytokines in 3T3-L1 adipocytes occurs as a result of specific degradation of LIFR via a lysosome-mediated pathway. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc

A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes

Copyright @ 2012, American Society for Microbiology.Human coronaviruses are associated with upper respiratory tract infections that occasionally spread to the lungs and other organs. Although airway epithelial cells represent an important target for infection, the respiratory epithelium is also composed of an elaborate network of dendritic cells (DCs) that are essential sentinels of the immune system, sensing pathogens and presenting foreign antigens to T lymphocytes. In this report, we show that in vitro infection by human coronavirus 229E (HCoV-229E) induces massive cytopathic effects in DCs, including the formation of large syncytia and cell death within only few hours. In contrast, monocytes are much more resistant to infection and cytopathic effects despite similar expression levels of CD13, the membrane receptor for HCoV-229E. While the differentiation of monocytes into DCs in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 requires 5 days, only 24 h are sufficient for these cytokines to sensitize monocytes to cell death and cytopathic effects when infected by HCoV-229E. Cell death induced by HCoV-229E is independent of TRAIL, FasL, tumor necrosis factor alpha, and caspase activity, indicating that viral replication is directly responsible for the observed cytopathic effects. The consequence of DC death at the early stage of HCoV-229E infection may have an impact on the early control of viral dissemination and on the establishment of long-lasting immune memory, since people can be reinfected multiple times by HCoV-229E

Census of Self-Obscured Massive Stars in Nearby Galaxies with Spitzer: Implications for Understanding the Progenitors of SN 2008S-Like Transients

A new link in the causal mapping between massive stars and potentially fatal explosive transients opened with the 2008 discovery of the dust-obscured progenitors of the luminous outbursts in NGC 6946 and NGC 300. Here we carry out a systematic mid-IR photometric search for massive, luminous, self-obscured stars in four nearby galaxies: M33, NGC 300, M81, and NGC 6946. For detection, we use only the 3.6 micron and 4.5 micron IRAC bands, as these can still be used for multi-epoch Spitzer surveys of nearby galaxies (=<10 Mpc). We combine familiar PSF and aperture-photometry with an innovative application of image subtraction to catalog the self-obscured massive stars in these galaxies. In particular, we verify that stars analogous to the progenitors of the NGC 6946 (SN 2008S) and NGC 300 transients are truly rare in all four galaxies: their number may be as low as ~1 per galaxy at any given moment. This result empirically supports the idea that the dust-enshrouded phase is a very short-lived phenomenon in the lives of many massive stars and that these objects constitute a natural extension of the AGB sequence. We also provide mid-IR catalogs of sources in NGC 300, M81, and NGC 6946.Comment: 21 pages, 15 figures, 11 tables. Accepted by ApJ on April 12, 2010. High resolution figures and full length versions of tables 6, 8 and 10 can be accessed at http://www.astronomy.ohio-state.edu/~khan/redstars

SN2007ax : An Extremely Faint Type Ia Supernova

We present multi-band photometric and optical spectroscopic observations of SN2007ax, the faintest and reddest Type Ia supernova (SNIa) yet observed. With M_B = -15.9 and (B-V)max = 1.2, this SN is over half a magnitude fainter at maximum light than any other SNIa. Similar to subluminous SN2005ke, SN2007ax also appears to show excess in UV emission at late time. Traditionally, Delta-m_15(B) has been used to parameterize the decline rate for SNeIa. However, the B-band transition from fast to slow decline occurs sooner than 15 days for faint SNeIa. Therefore we suggest that a more physically motivated parameter, the time of intersection of the two slopes, be used instead. Only by explaining the faintest (and the brightest) supernovae, we can thoroughly understand the physics of thermonuclear explosions. We suggest that future surveys should carefully design their cadence, depth, pointings and follow-up to find an unbiased sample of extremely faint members of this subclass of faint SNeIa.Comment: Accepted for publication in ApJ

Developing physical activity interventions for adults with spinal cord injury. Part 2: Motivational counseling and peer-mediated interventions for people intending to be active

Objective: The majority of people with spinal cord injury (SCI) do not engage in sufficient leisure-time physical activity (LTPA) to attain fitness benefits; however, many have good intentions to be active. This paper describes two pilot interventions targeting people with SCI who are insufficiently active but intend to be active (i.e., intenders ). Method: Study 1 examined the effects of a single, telephone-based counseling session on self-regulatory efficacy, intentions, and action plans for LTPA among seven men and women with paraplegia or tetraplegia. Study 2 examined the effects of a home-based strengthtraining session, delivered by a peer and a fitness trainer, on strength-training task self-efficacy, intentions, action plans, and behavior. Participants were 11 men and women with paraplegia. Results: The counseling session (Study 1) yielded medium- to large-sized increases in participants\u27 confidence to set LTPA goals and intentions to be active. The home visit (Study 2) produced medium- to large-sized increases in task self-efficacy, barrier self-efficacy, intentions, action planning, and strength-training behavior from baseline to 4 weeks after the visit. Conclusions/Implications: Study 1 findings provide preliminary evidence that a single counseling session can impact key determinants of LTPA among intenders with SCI. Study 2 findings demonstrate the potential utility of a peer-mediated, home-based strength training session for positively influencing social cognitions and strength-training behavior. Together, these studies provide evidence and resources for intervention strategies to promote LTPA. among intenders with SCI, a population for whom LTPA interventions and resources are scarcely available. © 2013 American Psychological Association

The destruction and survival of dust in the shell around SN 2008S

SN 2008S erupted in early 2008 in the grand design spiral galaxy NGC 6946. The progenitor was detected by Prieto et al. in Spitzer Space Telescope images taken over the four years prior to the explosion, but was not detected in deep optical images, from which they inferred a self-obscured object with a mass of about 10 Msun. We obtained Spitzer observations of SN 2008S five days after its discovery, as well as coordinated Gemini and Spitzer optical and infrared observations six months after its outburst. We have constructed radiative transfer dust models for the object before and after the outburst, using the same r^-2 density distribution of pre-existing amorphous carbon grains for all epochs and taking light-travel time effects into account for the early post-outburst epoch. We rule out silicate grains as a significant component of the dust around SN 2008S. The inner radius of the dust shell moved outwards from its pre-outburst value of 85 AU to a post-outburst value of 1250 AU, attributable to grain vaporisation by the light flash from SN 2008S. Although this caused the circumstellar extinction to decrease from Av = 15 before the outburst to 0.8 after the outburst, we estimate that less than 2% of the overall circumstellar dust mass was destroyed. The total mass-loss rate from the progenitor star is estimated to have been (0.5-1.0)x10^-4 Msun yr^-1. The derived dust mass-loss rate of 5x10^-7 Msun yr^-1 implies a total dust injection into the ISM of up to 0.01 Msun over the suggested duration of the self-obscured phase. We consider the potential contribution of objects like SN 2008S to the dust enrichment of galaxies.Comment: 9 pages, 7 figures, 3 tables. rv2. To appear in MNRA

NKG2D and Its Ligand MULT1 Contribute to Disease Progression in a Mouse Model of Multiple Sclerosis

NKG2D is an activating receptor expressed on the surface of immune cells including subsets of T lymphocytes. NKG2D binds multiple ligands (NKG2DL) whose expression are differentially triggered in a cell type and stress specific manner. The NKG2D-NKG2DL interaction has been involved in autoimmune disorders but its role in animal models of multiple sclerosis (MS) remains incompletely resolved. Here we show that NKG2D and its ligand MULT1 contribute to the pathobiology of experimental autoimmune encephalomyelitis (EAE). MULT1 protein levels are increased in the central nervous system (CNS) at EAE disease peak; soluble MULT1 is elevated in the cerebrospinal fluid of both active and passive EAE. We establish that such soluble MULT1 enhances effector functions (e.g., IFNγ production) of activated CD8 T lymphocytes from wild type but not from NKG2D-deficient (Klrk1−/−) mice in vitro. The adoptive transfer of activated T lymphocytes from wild type donors induced a significantly reduced EAE disease in Klrk1−/− compared to wild type (Klrk1+/+) recipients. Characterization of T lymphocytes infiltrating the CNS of recipient mice shows that donor (CD45.1) rather than endogenous (CD45.2) CD4 T cells are the main producers of key cytokines (IFNγ, GM-CSF). In contrast, infiltrating CD8 T lymphocytes include mainly endogenous (CD45.2) cells exhibiting effector properties (NKG2D, granzyme B and IFNγ). Our data support the notion that endogenous CD8 T cells contribute to passive EAE pathobiology in a NKG2D-dependent manner. Collectively, our results point to the deleterious role of NKG2D and its MULT1 in the pathobiology of a MS mouse model