Incapacitation of IRF3
Production of type I interferon, a process that requires activation of interferon-response factor 3 (IRF3), is essential for the induction of an antiviral state. In Cell Host & Microbe, Hwang et al. show that a herpesvirus protein antagonizes IRF3 activation. A variant of murine γ-herpesvirus 68 (MHV-68) with a mutant ORF36 protein shows less acute replication and delayed establishment of latency in wild-type mice but normal replication and latency in mice lacking the interferon-α (IFN-α) receptor. ORF36 suppresses IRF3-driven transcription of the Ifnb1 promoter by directly blocking interaction between active IRF3 and the CBP transcriptional coactivator. A MHV-68 virus expressing mutant ORF36 induces less production of IFN-β and fails to establish latency in wild-type mice. ORF36 proteins from several herpesviruses suppress Ifnb1 transcription, which suggests that ORF36 represents an evolutionarily conserved viral evasion protein. CB
CD93: in it for the long term
Some antibody-secreting plasma cells survive for long periods in the bone marrow. In the Proceedings of the National Academy of Sciences, Acha-Orbea and colleagues investigate the influence of the surface protein CD93 on the function of long-lived plasma cells. Immunization with T cell–dependent or T cell–independent antigen triggers the appearance of a subset of CD93+CD138+ antibody-secreting cells. Compared with cells expressing neither CD93 nor CD138, or either CD93 or CD138, these CD93+CD138+ cells release more class-switched antibody and express a transcription factor profile indicative of more-advanced plasma cell differentiation. The serum of Cd93−/− mice contains wild-type amounts of antigen-specific immunoglobulin 7–10 days after immunization but less than wild-type amounts 20–30 days later. At 30 days after immunization, fewer Cd93−/− than wild-type antigen-specific plasma cells are present in the bone marrow. Additional work is needed to understand how CD93 optimizes the homeostasis of long-lived plasma cells in the bone marrow. CB
Augmenting viral persistence
IL-17-producing T helper cells (TH-17 cells) are linked to various autoimmune conditions and to protection against extracellular bacterial or fungal diseases. In the Journal of Experimental Medicine, Kim and colleagues investigate the involvement of TH-17 cells in persistent viral infection. Infection with Theiler's murine encephalomyelitis virus induces more TH-17 cells both in vitro and in vivo in an IL-6-dependent way. Higher IL-17 concentrations augment viral persistence and disease pathogenesis by increasing production of IL-6 and the chemokines KC and MCP-1, which protects virus-infected cells from apoptosis and impedes the cytolytic function of virus-specific CD8+ T cells. Treatment of mice with antibodies to IL-17 reverses this effect. It is unclear whether TH-17 cells also promote other persistent viral infections in other chronic diseases. JDKW
B helper cells
Helper T cells contribute to the generation of high-affinity antibodies by B cells, but whether that 'help' is reciprocal remains unclear. In Immunity, Lund and colleagues show that B cell help is required for efficient T effector memory responses to the parasite Heligomosomoides polygyrus. Recall responses to parasitic infection require both antigen-specific antibody production and cytokines provided by the effector B cells. Primed B cells, acting as antigen-presenting cells to memory CD4+ T cells, supply the interleukin 2 (IL-2) needed to mount effective secondary responses and clear the parasite. These 'Be2' effector B cells provide additional cytokines, such as tumor necrosis factor and IL-4; however, Il2−/− B cells fail to reconstitute lasting antiparasitic immunity in B cell–deficient mice. Future work should clarify the context of the Be2 cell–T cell interaction required for antiparasitic immunity. LAD
Danger receptor
A subset of CD8α dendritic cells can phagocytose necrotic cell material and cross-prime CD8+ T cells against cell-associated antigens. In Nature, Reis e Sousa and colleagues show that the C-type lectin receptor CLEC9A is critical for this process. CLEC9A deficiency or antibody blockade does not affect phagocytosis of necrotic material but substantially diminishes cross-priming by CD8α+ dendritic cells of dead-cell-associated antigens in vitro and in vivo. The cytoplasmic tail of CLEC9A contains a 'hemITAM' motif with a tyrosine residue at position 7 critical for recruitment and activation of the tyrosine kinase Syk. Consistent with that, substitution of this tyrosine residue also blocks cross-priming. These data therefore identify CLEC9A as a receptor that couples necrosis to the innate immune system. Although the ligand of CLEC9A has not been identified, preliminary experiments suggest that the ligand is a ubiquitous preformed acid-labile protein that is normally sequestered in healthy cells. JDKW
Combating flu
The inherent mutability of influenza virus replication poses a tremendous hurdle to the development of vaccines that elicit neutralizing antibodies. In Nature Structural & Molecular Biology and Science, researchers describe the identification of broadly neutralizing antibodies that recognize the fusogenic stalk region of influenza's hemagglutinin. Despite starting with different 'library' sources, Marasco and colleagues and Ekiert et al. identify human antibodies that have common interaction properties with a hydrophobic pocket in hemagglutinin. Key aromatic residues (phenylalanine and tyrosine) and methionine residues located in the immunoglobulin heavy chain contact the viral fusion peptide-stalk region. This stalk region, which undergoes substantial conformational reorganization to allow viral entry after endosomal acidification, is highly conserved among influenza subtypes, such as the avian H5NI and 1918 Spanish H1N1 viruses. Hence, structural requirements for this fusogenic property may constrain mutations to maintain viral viability. Notably, the newly identified antibodies protect mice from lethal challenge by many influenza viruses. These findings thus represent a breakthrough in combating seasonal influenza and possibly pandemic flu. LAD
Nat. Struct. Mol. Biol. (22 February 2009) doi:10.1038/nsmb.1566 & Science (26 February 2009) doi:10.1126/science.1171491
Written by Christine Borowski, Laurie A. Dempsey & Jamie D.K. Wilson
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Research Highlights. Nat Immunol 10, 373 (2009). https://doi.org/10.1038/ni0409-373
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DOI: https://doi.org/10.1038/ni0409-373
