1,456 research outputs found
Protective Immunity Does Not Correlate with the Hierarchy of Virus-specific Cytotoxic T Cell Responses to Naturally Processed Peptides
Infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV) stimulates major histocompatibility complex class I–restricted cytotoxic T cells (CTLs), which normally resolve the infection. Three peptide epitopes derived from LCMV have been shown to bind the mouse class I molecule H-2 Db and to stimulate CTL responses in LCMV-infected mice. This report describes the identity and abundance of each CTL epitope after their elution from LCMV-infected cells. Based on this information, peptide abundance was found to correlate with the magnitude of each CTL response generated after infection with LCMV. Subsequent experiments, performed to determine the antiviral capacity of each CTL specificity, indicate that the quantitative hierarchy of CTL activity does not correlate with the ability to protect against LCMV infection. This report, therefore, indicates that immunodominant epitopes should be defined, not only by the strength of the CTL response that they stimulate, but also by the ability of the CTLs to protect against infection
Medicare for all
OBJECTIVES: Interferon (IFN) alpha is a key immunoregulatory cytokine secreted by activated plasmacytoid dendritic cells (PDC) that constitute less than 1% of leucocytes. IFNalpha plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Nevertheless, the natural IFNalpha inducers in SLE as well as the different IFNalpha secreting cell types are only partially characterised. METHODS: Chromatin was purified from calf thymus. Human peripheral blood mononuclear cells (PBMC), neutrophils and mouse bone marrow neutrophils were purified and cultured with different stimuli. IFNalpha production was estimated by flow cytometry, ELISA and a bioassay, and gene expression by quantitative real time PCR. Neutrophil activation and NETosis were analysed by flow cytometry, ELISA and confocal microscopy. RESULTS: Neutrophils produced a bioactive IFNalpha on stimulation with purified chromatin. IFNalpha secretion was observed with steady state neutrophils purified from 56 independent healthy individuals and autoimmune patients in response to free chromatin and not chromatin containing immune complexes. Chromatin induced IFNalpha secretion occurred independently of Toll-like receptor 9 (TLR9). Neutrophil priming by granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor or IFNalpha was not necessary but PBMC sustained IFNalpha secretion by neutrophils. PDC were 27 times more efficient than neutrophils but blood neutrophils were 100 times more frequent than PDC. Finally, neutrophil activation by chromatin was associated with NETosis and DNA sensor upregulation. CONCLUSIONS: Neutrophils have the capability of producing IFNalpha on selective triggering, and we identified a natural lupus stimulus involved, unveiling a new mechanism involved in SLE. Neutrophils represent another important source of IFNalpha and important targets for future therapies aimed at influencing IFNalpha levels
Class I major histocompatibility complexes loaded by a periodate trigger
Class I major histocompatibility complexes (MHCs) present peptide ligands on the cell surface for recognition by appropriate cytotoxic T cells. The unstable nature of unliganded MHC necessitates the production of recombinant class I complexes through in vitro refolding reactions in the presence of an added excess of peptides. This strategy is not amenable to high-throughput production of vast collections of class I complexes. To address this issue, we recently designed photocaged MHC ligands that can be cleaved by a UV light trigger in the MHC bound state under conditions that do not affect the integrity of the MHC structure. The results obtained with photocaged MHC ligands demonstrate that conditional MHC ligands can form a generally applicable concept for the creation of defined peptide−MHCs. However, the use of UV exposure to mediate ligand exchange is unsuited for a number of applications, due to the lack of UV penetration through cell culture systems and due to the transfer of heat upon UV irradiation, which can induce evaporation. To overcome these limitations, here, we provide proof-of-concept for the generation of defined peptide−MHCs by chemical trigger-induced ligand exchange. The crystal structure of the MHC with the novel chemosensitive ligand showcases that the ligand occupies the expected binding site, in a conformation where the hydroxyl groups should be reactive to periodate. We proceed to validate this technology by producing peptide−MHCs that can be used for T cell detection. The methodology that we describe here should allow loading of MHCs with defined peptides in cell culture devices, thereby permitting antigen-specific T cell expansion and purification for cell therapy. In addition, this technology will be useful to develop miniaturized assay systems for performing high-throughput screens for natural and unnatural MHC ligands
Constraints on the pMSSM from searches for squarks and gluinos by ATLAS
We study the impact of the jets and missing transverse momentum SUSY analyses
of the ATLAS experiment on the phenomenological MSSM (pMSSM). We investigate
sets of SUSY models with a flat and logarithmic prior in the SUSY mass scale
and a mass range up to 1 and 3 TeV, respectively. These models were found
previously in the study 'Supersymmetry without Prejudice'. Removing models with
long-lived SUSY particles, we show that 99% of 20000 randomly generated pMSSM
model points with a flat prior and 87% for a logarithmic prior are excluded by
the ATLAS results. For models with squarks and gluinos below 600 GeV all models
of the pMSSM grid are excluded. We identify SUSY spectra where the current
ATLAS search strategy is less sensitive and propose extensions to the inclusive
jets search channel
Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host
The cellular adaptive immune response plays a key role in resolving influenza
infection. Experiments where individuals are successively infected with
different strains within a short timeframe provide insight into the underlying
viral dynamics and the role of a cross-reactive immune response in resolving an
acute infection. We construct a mathematical model of within-host influenza
viral dynamics including three possible factors which determine the strength of
the cross-reactive cellular adaptive immune response: the initial naive T cell
number, the avidity of the interaction between T cells and the epitopes
presented by infected cells, and the epitope abundance per infected cell. Our
model explains the experimentally observed shortening of a second infection
when cross-reactivity is present, and shows that memory in the cellular
adaptive immune response is necessary to protect against a second infection.Comment: 35 pages, 12 figure
Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC
The uncertainty on the calorimeter energy response to jets of particles is
derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the
calorimeter response to single isolated charged hadrons is measured and
compared to the Monte Carlo simulation using proton-proton collisions at
centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009
and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter
response to specific types of particles (positively and negatively charged
pions, protons, and anti-protons) is measured and compared to the Monte Carlo
predictions. Finally, the jet energy scale uncertainty is determined by
propagating the response uncertainty for single charged and neutral particles
to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3%
for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table,
submitted to European Physical Journal
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