101 research outputs found
Antigenic Sequences of Poliovirus Recognized by T Cells: Serotype-Specific Epitopes on VP1 and VP3 and Cross-Reactive Epitopes on VP4 Defined by Using CD4+ T-Cell Clones
A panel of poliovirus-specific murine CD4+ T-cell clones has been established from both BALB/c (H-2d) and
CBA (H-2k) mice immunized with Sabin vaccine strains of poliovirus serotype 1, 2, or 3. T-cell clones were
found to be either serotype specific or cross-reactive between two or all three serotypes. Specificity analysis
against purified poliovirus proteins demonstrated that T-cell clones recognized determinants on the surface
capsid proteins VP1, VP2, and VP3 and the internal capsid protein VP4. Panels of overlapping synthetic
peptides were used to identify eight distinct T-cell epitopes. One type 3-specific T-cell clone recognized an
epitope within amino acids 257 and 264 of VP1. Three T-cell epitopes corresponding to residues 14 to 28, 189
to 203, and 196 to 210 were identified on VP3 of poliovirus type 2. The remaining four T-cell epitopes were
mapped to an immunodominant region of VP4, encompassed within residues 6 and 35 and recognized by both
H-2Z and H-2k mice. The epitopes on VP4 were conserved between serotypes, and this may account for the
predominantly cross-reactive poliovirus-specific T-cell response observed with polyclonal T-cell populations. In
contrast, T-cell clones that recognize epitopes on VP1 or VP3 were largely serotype specific; single or multiple
amino acid substitutions were found to be critical for T-cell recognition
A crucial role for interleukin (IL)-1 in the induction of IL-17âproducing T cells that mediate autoimmune encephalomyelitis
It was recently demonstrated that interleukin (IL)-23âdriven IL-17âproducing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type Iâdeficient (IL-1RIâ/â) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RIâ/â compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RIâ/â mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RIâ/â mice, and IL-23âinduced IL-17 production was substantially enhanced by IL-1α or IL-1ÎČ, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor ÎșB, and novel protein kinase C isoforms in IL-1â and IL-23âmediated IL-17 production. Tumor necrosis factor α also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE
Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis
Murine inflammatory caspase-11 has an important role in intestinal epithelial inflammation and barrier function. Activation of the non-canonical inflammasome, mediated by caspase-11, serves as a regulatory pathway for the production of the proinflammatory cytokines IL-1ÎČ and IL-18, and has a key role in pyroptotic cell death. We have previously demonstrated a protective role for caspase-11 during dextran sulphate sodium (DSS)-induced colitis, however the importance of caspase-11 during colorectal tumour development remains unclear. Here, we show that Casp11â/â mice are highly susceptible to the azoxymethane (AOM)-DSS model of colitis-associated cancer (CAC), compared to their wild type (WT) littermates. We show that deficient IL-18 production occurs at initial inflammation stages of disease, and that IL-1ÎČ production is more significantly impaired in Casp11â/â colons during established CAC. We identify defective STAT1 activation in Casp11â/â colons during disease progression, and show that IL-1ÎČ signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells. These findings uncover an anti-tumour role for the caspase-11 and the non-canonical inflammasome during CAC, and suggest a critical role for caspase-11, linking IL-1ÎČ and STAT1 signalling pathways
HIV p24-Specific Helper T Cell Clones From Immunised Primates Recognize Highly Conserved Regions of HIV-l
We have investigated Th cell recognition of the
HIV core protein p24 by using CD4+ T cell clones
derived from cynomolgus macaques immunized
with hybrid HIV p24:Ty virus-like particles (VLP). T
cell lines from two immunized animals responded
to p24:Ty-VLP, control Ty-VLP, purified p24, and
whole inactivated HIV, indicating the presence of T
cells specific for p24 as well as the Ty carrier protein.
The HIV determinants recognized by the T cell
lines were identified by using a series of overlapping
peptides synthesized according to the sequence of
p24. Both T cell lines recognized peptide 11 (amino
acids 235-249) and peptide 14 (amino acids 265-
279). In addition, one T cell line also responded to
peptide 9 (amino acids 215-229). Definitive identification
of two T cell epitopes on p24 was confirmed
at the clonal level: from a total of four T cell clones
generated from one of the T cell lines, two respond
specifically to peptide 11 and two to peptide 14. The
T cell clones were CD4' and MHC class 11-restricted
and secreted IL-2 in response to stimulation with
purified p24, inactivated HIV or a single synthetic
peptide. The specificityof the Th clones for variant
peptides demonstrated cross-reactivity with two
simian immunodeficiency virus isolates, but only
limited responses to HIV-2 sequences. However, the
Th cell epitopes identified on p24 are highly conserved
between 12 HIV-1 isolates and were recognized
by both of the immunized primates. These
sequences may therefore be useful for priming a
broadly reactive immune response to HIV-1
A population of proinflammatory T cells coexpresses αÎČ and γΎ T cell receptors in mice and humans
T cells are classically recognized as distinct subsets that express αÎČ or γΎ TCRs. We identify a novel population of T cells that coexpress αÎČ and γΎ TCRs in mice and humans. These hybrid αÎČ-γΎ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αÎČ TCRâmediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRÎŽ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-Îł, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1ÎČ and IL-23. Hybrid αÎČ-γΎ T cells were transcriptomically distinct from conventional γΎ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system
The âmosaic habitatâ concept in human evolution: past and present
The habitats preferred by hominins and other species are an important theme in palaeoanthropology, and the âmosaic habitatâ (also referred to as habitat heterogeneity) has been a central concept in this regard for the last four decades. Here we explore the development of this concept â loosely defined as a range of different habitat types, such as woodlands, riverine forest and savannah within a limited spatial areaâ in studies of human evolution in the last sixty years or so. We outline the key developments that took place before and around the time when the term âmosaicâ came to wider palaeoanthropological attention. To achieve this we used an analysis of the published literature, a study of illustrations of hominin evolution from 1925 onwards and an email survey of senior researchers in palaeoanthropology and related fields. We found that the term mosaic starts to be applied in palaeoanthropological thinking during the 1970âs due to the work of a number of researchers, including Karl Butzer and Glynn Isaac , with the earliest usage we have found of âmosaicâ in specific reference to hominin habitats being by Adriaan Kortlandt (1972). While we observe a steady increase in the numbers of publications reporting mosaic palaeohabitats, in keeping with the growing interest and specialisation in various methods of palaeoenvironmental reconstruction, we also note that there is a lack of critical studies that define this habitat, or examine the temporal and spatial scales associated with it. The general consensus within the field is that the concept now requires more detailed definition and study to evaluate its role in human evolution
The ATLAS trigger system for LHC Run 3 and trigger performance in 2022
The ATLAS trigger system is a crucial component of the ATLAS experiment at the LHC. It is responsible for selecting events in line with the ATLAS physics programme. This paper presents an overview of the changes to the trigger and data acquisition system during the second long shutdown of the LHC, and shows the performance of the trigger system and its components in the proton-proton collisions during the 2022 commissioning period as well as its expected performance in proton-proton and heavy-ion collisions for the remainder of the third LHC data-taking period (2022â2025)
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