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The B7 family member B7-H3 (CD276) plays important roles in immune responses. However, the function of B7-H3 remains controversial. We found that murine B7-H3 specifically bound to Triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2, TREML2). TLT-2 was expressed on CD8⁺ T cells constitutively and on activated CD4⁺ T cells. Stimulation with B7-H3 transfectants preferentially up-regulated the proliferation and IFN-γ production of CD8⁺ T cells. Transduction of TLT-2 into T cells resulted in enhanced IL-2 and IFN-γ production via interactions with B7-H3. Blockade of the B7-H3:TLT-2 pathway with a mAb against B7-H3 or TLT-2 efficiently inhibited contact hypersensitivity responses. Our results demonstrate a direct interaction between B7-H3 and TLT-2 that preferentially enhances CD8⁺ T cell activation.

Lanier and colleagues systematically define the transcriptome of mouse natural killer cells in several contexts, including activation states and relative to all other lymphocyte and myeloid populations profiled by the Immunological Genome Project consortium. Using whole-genome microarray data sets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK cells and T cells than between any other leukocytes, distinguished by their shared expression of genes encoding molecules with similar signaling functions. Whereas resting NK cells are known to share expression of a few genes with cytotoxic CD8 + T cells, our transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many encoding molecules with unknown functions. Resting NK cells demonstrate a 'preprimed' state compared with naive T cells, which allows NK cells to respond more rapidly to viral infection. Collectively, our data provide a global context for known and previously unknown molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.

The metallothionein-like, 23-amino-acid peptide NO-inducible nitrosothionein does not protect against heavy metal toxicity like its homologues, but instead helps relieve nitrosative stress by reaction of six cysteine residues to form SNO adducts, which are recycled back to thiols by thioredoxin. Nitric oxide (NO) is a toxic reactive nitrogen species that induces microbial adaption mechanisms. Screening a genomic DNA library identified a new gene, ntpA , that conferred growth tolerance upon Aspergillus nidulans against exogenous NO. The gene encoded a cysteine-rich 23-amino-acid peptide that reacted with NO and S -nitrosoglutathione to generate an S-nitrosated peptide. Disrupting ntpA increased amounts of cellular S -nitrosothiol and NO susceptibility. Thioredoxin and its reductase denitrosated the S-nitrosated peptide, decreased cellular S -nitrosothiol and conferred tolerance against NO, indicating peptide-mediated catalytic NO removal. The peptide binds copper( I ) in vitro but is dispensable for metal tolerance in vivo . NO but not metal ions induced production of the peptide and ntpA transcripts. We discovered that the thionein family of peptides has NO-related functions and propose that the new peptide be named NO-inducible nitrosothionein (iNT). The ubiquitous distribution of iNT-like polypeptides constitutes a potent NO-detoxifying mechanism that is conserved among various organisms.

What is the role and value of consortium biology in immunology? Here, the participants of the Immunological Genome Project share their thoughts on the benefits and shortcomings of 'big science' and discuss how the immunology community can profit from engaging in this type of discovery-led research. Although the field has a long collaborative tradition, immunology has made less use than genetics of 'consortium biology', wherein groups of investigators together tackle large integrated questions or problems. However, immunology is naturally suited to large-scale integrative and systems-level approaches, owing to the multicellular and adaptive nature of the cells it encompasses. Here, we discuss the value and drawbacks of this organization of research, in the context of the long-running 'big science' debate, and consider the opportunities that may exist for the immunology community. We position this analysis in light of our own experience, both positive and negative, as participants of the Immunological Genome Project.

Using whole-genome microarray datasets of the Immunological Genome Project, we demonstrate a closer transcriptional relationship between NK and T cells than any other leukocytes, distinguished by their expression of similar signaling functions. While resting NK cells were known to share expression of a few genes with cytotoxic CD8+ T cells, transcriptome-wide analysis demonstrates that the commonalities extend to hundreds of genes, many with unknown functions. The NK cell response to viral infection is dampened relative to cytotoxic CD8+ T cells, in part due to their “pre-primed” state. Collectively, the data provide global context for known and novel molecular aspects of NK cell identity and function by delineating the genome-wide repertoire of gene expression of NK cells in various states.

Nature Reviews Immunology 12, 734–740 (2012) In the version of this Perspectives article that was originally published, the surname of an author listed as a member of the Immunological Genome Project was misspelt. The correct spelling is Cipolletta (and not Cipoletta, as in the original). The authors apologize for this error, which has been corrected in the online HTML and PDF versions of the article.

Background During the chemical and biochemical decomposition of lignocellulosic biomasses, lignin is highly recalcitrant. Genetic transformation of plants to qualitatively and/or quantitatively modify lignin may reduce these recalcitrant properties. Efficient discovery of genes to achieve lignin manipulation is thus required. Results To screen for new genes to reduce lignin recalcitrance, we heterologously expressed 50 enzymatic genes under the control of a cinnamate 4-hydroxylase (C4H) gene promoter, derived from a hybrid aspen, which is preferentially active in tissues with lignified cell walls in Arabidopsis plants. These genes encode enzymes that act on metabolites in shikimate, general phenylpropanoid, flavonoid, or monolignol biosynthetic pathways. Among these genes, 30, 18, and 2 originated from plants, bacteria, and fungi, respectively. In our first screening step, 296 independent transgenic plants (T1 generation) harboring single or multiple transgenes were generated from pools of seven Agrobacterium strains used for conventional floral-dip transformation. Wiesner and Mäule staining patterns in the stems of the resultant plants revealed seven and nine plants with apparent abnormalities in the two respective staining analyses. According to genomic PCR and subsequent direct sequencing, each of these 16 plants possessed a gene encoding either coniferaldehyde dehydrogenase (calB), feruloyl-CoA 6′-hydroxylase (F6H1), hydroxycinnamoyl-CoA hydratase/lyase (couA), or ferulate 5-hydroxylase (F5H), with one transgenic plant carrying both calB and F6H1. The effects of these genes on lignin manipulation were confirmed in individually re-created T1 transgenic Arabidopsis plants. While no difference in lignin content was detected in the transgenic lines compared with the wild type, lignin monomeric composition was changed in the transgenic lines. The observed compositional change in the transgenic plants carrying calB, couA, and F5H led to improved sugar release from cell walls after alkaline pretreatment. Conclusions Simple colorimetric characterization of stem lignin is useful for simultaneous screening of many genes with the potential to reduce lignin recalcitrance. In addition to F5H, the positive control, we identified three enzyme-coding genes that can function as genetic tools for lignin manipulation. Two of these genes (calB and couA) accelerate sugar release from transgenic lignocelluloses.

Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Inter-annual variation in the feeding habits and food sources of Japanese sardine and mackerel at age-0 and age-1+ caught in the Kuroshio-Oyashio transition zone of the Western North Pacific were investigated based on analyses of bulk stable isotopes ( δ 13 C, δ 15 N) and amino acid nitrogen isotopes ( δ 15 N AA ). Differences in δ 13 C and δ 15 N between Japanese sardine and mackerel were small for age-0, and inter-annual variation trends were similar, suggesting they depend on similar food sources in the same food web at this age. In contrast, inter-annual variation in δ 13 C and δ 15 N were significantly different between both species at age-1+, and both δ 15 N of phenylalanine ( δ 15 N Phe : an indicator of nitrogen source) and trophic position estimated from δ 15 N AA (TP AA ) were higher in mackerel, suggesting that the two species depend on distinct food webs as they age. Inter-annual variations in δ 15 N Phe were considered to have different causes for the two species; differences in food web structure due to the degree of southward intrusion of the Oyashio Current for Japanese sardine, compared to a shift in migration area and depth for mackerel. Furthermore, competition for food due to the recent increases in the population densities of both fishes appeared to be reflected in increased TP AA of mackerel. Although they are caught in the same region, the mechanism of variation in food sources differs because of differences in migration area, depth, and feeding habits. Differences in the feeding habits of Japanese sardine and mackerel may affect trophic status and spawning characteristics, potentially leading to different shifts in stock abundances.

We aim to elucidate factors to aid in the prediction of cytomegalovirus viremia during the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We conducted a single-center, retrospective, observational study of 35 patients with newly diagnosed AAV. Factors associated with the development of CMV viremia were investigated via a logistic regression analysis. The CMV antigenemia test was performed in 25 patients (71%), of whom 15 (60%) were diagnosed with CMV viremia. Of these 15 patients, 5 developed a CMV infection. The total protein, hemoglobin, platelet count and lymphocyte counts at the time of the CMV antigenemia test were significantly lower in patients who developed CMV viremia. In addition, total protein, hemoglobin, platelet count and lymphocyte count also presented significantly decreasing trends in the following order: patients who did not develop CMV viremia, patients who developed CMV viremia without any symptoms, and patients who developed CMV infection. All patients with CMV recovered. In conclusion, the total protein, hemoglobin, platelet count and lymphocyte count may be useful markers for the prediction of CMV viremia and infection after the start of induction of immunosuppressive therapy for patients with AAV.