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Tissue-resident memory (TRM) CD8+ T cells are largely derived from recently activated effector T cells, but the mechanisms that control the extent of TRM differentiation within tissue microenvironments remain unresolved. Here, using an IFNγ-YFP reporter system to identify CD8+ T cells executing antigen-dependent effector functions, we define the transcriptional consequences and functional mechanisms controlled by TCR-signaling strength that occur within the skin during viral infection to promote TRM differentiation. TCR-signaling both enhances CXCR6-mediated migration and suppresses migration toward sphingosine-1-phosphate, indicating the programming of a 'chemotactic switch' following secondary antigen encounter within non-lymphoid tissues. Blimp1 was identified as the critical target of TCR re-stimulation that is necessary to establish this chemotactic switch and for TRM differentiation to efficiently occur. Collectively, our findings show that access to antigen presentation and strength of TCR-signaling required for Blimp1 expression establishes the chemotactic properties of effector CD8+ T cells to promote residency within non-lymphoid tissues. CD8+ T cells are found within peripheral tissues including the skin. Here, the authors use an interferon-gamma reporter system and viruses expressing agonistic peptides of varying affinities to investigate how T cell receptor signaling strength changes the chemotactic properties of effector CD8+ T cells to promote tissue-residency. [ABSTRACT FROM AUTHOR]

Avian influenza A(H7N9) epidemics have a fatality rate of approximately 40%. Previous studies reported that low pathogenic avian influenza (LPAI)-derived candidate vaccine viruses (CVVs) are poorly immunogenic. Here, we assess the immunogenicity and efficacy of a highly pathogenic avian influenza (HPAI) A/Guangdong/17SF003/2016 (GD/16)-extracted hemagglutinin (eHA) vaccine. GD/16 eHA induces robust H7-specific antibody responses in mice with a marked adjuvant antigen-sparing effect. Mice immunized with adjuvanted GD/16 eHA are protected from the lethal LPAI and HPAI H7N9 challenges, in stark contrast to low antibody titers and high mortality in mice receiving adjuvanted LPAI H7 eHAs. The protection correlates well with the magnitude of the H7-specific antibody response (IgG and microneutralization) or HA group 2 stem-specific IgG. Inclusion of adjuvanted GD/16 eHA in heterologous prime-boost improves the immunogenicity and protection of LPAI H7 HAs in mice. Our findings support the inclusion of GD/16-derived CVV in the pandemic preparedness vaccine stockpile. [ABSTRACT FROM AUTHOR]

Translational fidelity, essential for protein and cell function, requires accurate transfer RNA (tRNA) aminoacylation. Purified aminoacyl-tRNA synthetases exhibit a fidelity of one error per 10,000 to 100,000 couplings. The accuracy of tRNA aminoacylation in vivo is uncertain, however, and might be considerably lower. Here we show that in mammalian cells, approximately 1% of methionine (Met) residues used in protein synthesis are aminoacylated to non-methionyl-tRNAs. Remarkably, Met-misacylation increases up to tenfold upon exposing cells to live or non-infectious viruses, toll-like receptor ligands or chemically induced oxidative stress. Met is misacylated to specific non-methionyl-tRNA families, and these Met-misacylated tRNAs are used in translation. Met-misacylation is blocked by an inhibitor of cellular oxidases, implicating reactive oxygen species (ROS) as the misacylation trigger. Among six amino acids tested, tRNA misacylation occurs exclusively with Met. As Met residues are known to protect proteins against ROS-mediated damage, we propose that Met-misacylation functions adaptively to increase Met incorporation into proteins to protect cells against oxidative stress. In demonstrating an unexpected conditional aspect of decoding mRNA, our findings illustrate the importance of considering alternative iterations of the genetic code. [ABSTRACT FROM AUTHOR]

Making discoveries is the most important part of being a scientist, and also the most fun. Young scientists need to develop the experimental and mental skill sets that enable them to make discoveries, including how to recognize and exploit serendipity when it strikes. Here, I provide practical advice to young scientists on choosing a research topic, designing, performing and interpreting experiments and, last but not least, on maintaining your sanity in the process. [ABSTRACT FROM AUTHOR]

Biomedical research has never been more intellectually exciting or practically important to society. Ironically, pursuing a career as a biomedical scientist has never been more difficult. Here I provide unvarnished advice for young biomedical scientists on the difficulties that lie ahead and on how to find the right laboratories for training in the skills that you will need to succeed. Although my advice is geared towards succeeding in the United States, many aspects apply to other countries. [ABSTRACT FROM AUTHOR]

It is uncertain how antiviral lymphocytes are activated in draining lymph nodes, the site where adaptive immune responses are initiated. Here, using intravital microscopy we show that after infection of mice with vaccinia virus (a large DNA virus) or vesicular stomatitis virus (a small RNA virus), virions drained to the lymph node and infected cells residing just beneath the subcapsular sinus. Naive CD8+ T cells rapidly migrated to infected cells in the peripheral interfollicular region and then formed tight interactions with dendritic cells, leading to complete T cell activation. Thus, antigen presentation at the lymph node periphery, not at lymphocyte exit sites in deeper lymph node venules, as dogma dictates, has a dominant function in antiviral CD8+ T cell activation. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) detect and destroy cells displaying class I molecules of the major histocompatibility complex (MHC) that present oligopeptides derived from aberrant self or foreign proteins. Most class I peptide ligands are created from proteins that are degraded by proteasomes and transported, by the transporter associated with antigen processing, from the cytosol into the endoplasmic reticulum, where peptides bind MHC class I molecules and are conveyed to the cell surface. C2 CTLs, cloned from human CTLs infiltrating a renal cell carcinoma, kill cancer cells overexpressing fibroblast growth factor-5 (FGF-5). Here we show that C2 cells recognize human leukocyte antigen-A3 MHC class I molecules presenting a nine-residue FGF-5 peptide generated by protein splicing. This process, previously described strictly in plants and unicellular organisms, entails post-translational excision of a polypeptide segment followed by ligation of the newly liberated carboxy-terminal and amino-terminal residues. The occurrence of protein splicing in vertebrates has important implications for the complexity of the vertebrate proteome and for the immune recognition of self and foreign peptides. [ABSTRACT FROM AUTHOR]

MHC class I molecules bind short peptides and present them to CD8+ T cells. Contrary to textbook descriptions, the generation of MHC class-I-associated peptides from endogenous proteins is a highly dynamic and remarkably inefficient process. Here, we describe recent experiments that show how nascent and mature proteins are degraded into peptides that are trimmed, transported and trimmed again to enable presentation of a small portion of the generated peptides. By linking the failure rate of protein synthesis with antigen presentation, a rapid T-cell response is ensured, which is crucial in combating viral infections. Presentation on MHC class I molecules is achieved by less than 0.1% of the specific peptides that have survived intracellular destruction. The other peptides are converted into free amino acids that are used for recycling into new proteins. [ABSTRACT FROM AUTHOR]

CD8[sup +] T cells play an important role in immunity to viruses. Just how important these cells are is demonstrated by the evolution of viral strategies for blocking the generation or display of peptide-major histocompatibility complex class I complexes on the surfaces of virus-infected cells. Here, we focus on viral interference with antigen presentation; in particular we consider the importance (and difficulty) of establishing the evolutionary significance (that is, the ability to enhance viral transmission) of viral gene products that interfere with antigen presentation in vitro. [ABSTRACT FROM AUTHOR]

The rational design of vaccines that elicit CD8+ T cell responses requires knowledge of the identity of the antigen-presenting cell (APC), the location and time of presentation and the nature of the antigen presented by the APC. Here we address these questions for an antigen encoded by a recombinant vaccinia virus. We found that, following local infection, vaccinia virus infected macrophages and dendritic cells in draining lymph nodes. However, only the dendritic cells presented antigen to naïve CD8+ T cells, as determined by direct visualization of sectioned nodes by confocal microscopy. Presentation occurred as rapidly as 6 h after inoculation and quickly declined in parallel with the number of infected cells present in the nodes. These data provide direct evidence that virus-infected APCs prime naïve CD8+ T cells in vivo. [ABSTRACT FROM AUTHOR]

While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection. [ABSTRACT FROM AUTHOR]

Shows that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. Finding that in a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins.

The article presents a structural and functional analyses of neutralizing bodies against influenza virus H2 subtype of hemagglutinin (HA). It is inferred that the analyses may explain the disappearance of such HA subtype from circulation in the human population as well as may direct to a potential approach for antiflu therapeutics. The interaction between H2 and HA and three human monoclonal antibodies is described, through the use of X-ray crystallography.

The article presents research on the cross dressing of T cells to kill infected cells and provide immunity. Researchers found that these cells kills infected cells by cross-dressing or direct presentation. Moreover, they found that these cells have the ability to utilize information packets to control pathogens and to protect from virus.

The article presents a study on major histocompatibility complex (MHC) molecules. MHC molecules present oligopeptides peptide antigens from immunogenic proteins to activate T-cell responses. Synthetic oligopeptides chemically modified with environmentally sensitive fluorophores allow visualization of peptide binding to MHC molecules.

The article shows that activated dendritic cells fail to cross-prime CD8+ T cell responses. Viruses that infect professional antigen-presenting cells may have contributed to the evolution of cross-priming. Cross-priming of CD8+ T cells involves three specialized features of dendritic cells. In vitro activation of dendritic cells results in inhibition of cross-priming.

Investigates the mechanism behind defective protein secretion by CD8[sup +] T cells in patients with type 2 Hermansky-Pudlak syndrome (HPS2). Explanation of patients' susceptibility to infection through mutations in AP-3 that prevent movement of lytic granules along microtubules in CD8[sup +] T cells; Functions of cytokines released by CD8[sup +] T cells after being activated.

Focuses on the impact of T cells on pathogens. Way by which T cells battle against pathogens; Impact of T cells on antigen-presenting cells; Amount of T cells present in humans.

Discusses how microscopy is providing fresh insights in the field of immunology. Overview on dendritic cells; Green flourescent protein; Tubule polarization.