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Mouse IgG subclasses display a hierarchy of in vivo activities, with IgG2a and IgG2b showing the greatest protective and pathogenic properties. These enhanced activities result, in part, from their ability to bind to a novel, γ chain-dependent, activating IgG Fc receptor, FcγRIV. FcγRIV maps in the 75 kb genomic interval between FcγRII and FcγRIII; its expression is restricted to myeloid lineage cells,...
Anopheles gambiae uses effective immune responses, including phagocytosis, to fight microbial infection. We have developed a semiquantitative phagocytosis test and used it in conjunction with dsRNA gene silencing to test the in vivo roles of 71 candidate genes in phagocytosis of Escherichia coli and Staphylococcus aureus. Here, we show that inactivation of 26 genes changes the phagocytic activity...
The known IgG FcRs primarily mediate inflammation by interacting with IgG1, even though IgG2 isotypes tend to be more pathogenic. Nimmerjahn et al. (2005) have just identified a novel FcγR that binds IgG2 but not IgG1, potentially explaining differences in biological activity that are seen with various IgG isotypes (Nimmerjahn et al., 2005).
Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, was also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. We show by gene targeting that RIG-I is essential for induction of type I interferons (IFNs) after infection with...
When hepatitis B virus (HBV)-specific CD8 + cytotoxic T lymphocytes (CTLs) are adoptively transferred into HBV transgenic mice, they enter the liver, recognize antigen, secrete interferon γ (IFNγ), inhibit viral replication, and kill their target cells, causing hepatitis. In the current study, we examined the impact of antigen recognition on the evolution of the activation phenotype, antiviral...
Il4 and Il13, closely linked genes, are expressed monoallelically in TH2 cells. Four different approaches (RNA FISH, cultures from Il13T-Il4/Il13-G4 mice, cultures from heterozygous Il13-Il4 double knockout mice, and a highly selected set of BABL/c*CAST/Ei clones displaying strong Il4 allelic bias) were utilized to study monoallelic expression of Il4 and coexpression of Il4 and Il13 on the same chromosome...
Capsular polysaccharides enhance bacterial virulence. In this issue of Immunity, Haas et al. (2005) demonstrate a division of labor between the B-1 B cell subsets: natural antibodies from B-1a cells limit infection by Streptococcus pneumoniae, whereas B-1b cells generate the anticapsule-induced response that prevents fatal infection.
For developing T cells, coreceptor choice is matched to T cell antigen receptor (TCR) MHC specificity during positive selection in the thymus, but the mechanism remains uncertain. Here, we document that TCR-mediated positive selection signals inactivate the immature CD8 III enhancer in double positive (DP) thymocytes, explaining in part the cessation of CD8 coreceptor transcription that occurs...
B-1a and B-1b lymphocytes were found to exhibit specialized roles in providing immunity to Streptococcus pneumoniae and differ dramatically in their developmental requirements. Transgenic mice overexpressing CD19 (hCD19Tg) generated B-1a cells and natural antibodies that provided protection during infection, while CD19-deficient (CD19 −/− ) mice lacked B-1a cells, lacked natural antibodies,...
A number of modified histones, including acetylated H3 and H4 and phosphorylated H2AX (γH2AX), are associated with V(D)J recombination and class switch recombination (CSR). In contrast, little is known concerning the chromatin modifications associated with somatic hypermutation (SHM) in vivo. Here, we report that several modifications—including histone acetylation and H3-lysine 4 methylation—fail...
How CD4 + CD8 + thymocytes commit to CD4 helper versus CD8 cytotoxic lineages is a central unresolved question in developmental immunology. In this issue, Sarafova et al. (2005) show that engineering CD4 for shutoff immediately after positive selection misdirects cells to the cytotoxic lineage. The result highlights the distinction between positive selection and lineage commitment...
T cell priming to exogenous antigens reflects regulated antigen processing in dendritic cells, subsequent homing to lymph nodes, sustained interactions between T cells and antigen-bearing dendritic cells, and, ultimately, selective T cell activation and differentiation. In this study, we test the hypothesis that an intrinsic property of the class II:peptide complex is a key determinant that dictates...
Calcium modulating cyclophilin ligand (CAML) is a ubiquitously expressed protein implicated in T cell signaling, although its mechanism and physiologic role in the immune system are unknown. We show here that CAML is essential for peripheral T cell development. Inactivation of CAML in mouse thymocytes lowered the numbers of double-positive and single-positive thymocytes, concomitant with reduced positive...
CpG methylation of DNA silences TLR9-mediated innate immune recognition. In this issue of Immunity, Kariko et al. (2005) suggest that the innate immune recognition of RNA by TLR3, TLR7, or TLR8 is in fact controlled by modification of nucleotides, including methylation.
V(D)J recombination is a tightly controlled process of somatic recombination whose regulation is mediated in part by chromatin structure. Here, we report that RAG2 binds directly to the core histone proteins. The interaction with histones is observed in developing lymphocytes and within the RAG1/RAG2 recombinase complex in a manner that is dependent on the RAG2 C terminus. Amino acids within the plant...
Posttranscriptional regulatory mechanisms control TNFα expression through AU-rich elements in the 3′UTR of its mRNA. This is mediated through Erk and p38 MAP kinase signaling, although the mechanisms involved remain poorly understood. Here, we show that the MAP kinase signal-integrating kinases (Mnks), which are activated by both these pathways, regulate TNFα expression in T cells via the 3′UTR. A...
Engagement of the B cell antigen receptor (BCR) triggers the Ras cascade, but the biological role of the latter in B cell response is unknown. Here, we report that in T cell-dependent response, the role of the Ras cascade is confined to memory B cells and possibly marginal zone B cells. When Ras-dependent BCR signaling was impaired, the generation of IgG germinal center B cells was unaffected but...
The recruitment of basophils into the sites of allergic inflammation is often observed. However, no definitive evidence has been provided that basophils are crucially involved in the pathogenesis of chronic allergic disorders. Here, we show that basophils are responsible for the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. A single subcutaneous...
Type 1 diabetes (T1D) animal models such as the nonobese diabetic (NOD) mouse have improved our understanding of disease pathophysiology, but many candidate therapeutics identified therein have failed to prevent/cure human disease. We have performed a comprehensive evaluation of disease-modifying agents tested in the NOD mouse based on treatment timing, duration, study length, and efficacy. Interestingly,...
In this issue of Immunity, Anderson et al. provide another clue to the riddle that is Aire—why do human beings and mice lacking Aire develop diffuse and pathogenic autoimmunity? They find that Aire influences central tolerance not only by promoting the expression of peripheral self-proteins in thymic medullary epithelial cells (MECs) but also by furnishing these cells with the apparatus for effective...
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