Immunology highlights from the recent literature

    Worm defense

    Caenorhabditis elegans is a potentially useful model for genetic dissection of the innate immune response, but little is known about nematode host defense. In Current Biology, Mallo et al. identify a number of genes, including those encoding lectins and lysozymes, whose expression is increased after infection with Serratia marcescens. The TGF-β–related gene dbl-1 controls some of these genes, and, consistently, dbl mutants are more susceptible to bacterial infection. In Science, Kim et al. show that sek-1 and nsy-1—which encode a MAPKK and a MAPKKK, respectively—are required for resistance to Pseudomonas aeruginosa killing. The p38 ortholog pmk-1 functions downstream in this immune response. Thus, C. elegans, like Drosophila, can induce antibacterial defenses and could prove useful for the genetic analysis of innate immunity.

    Curr. Biol. 12, 1209–1214 (2002); Science 297, 623–626 (2002)

    Attacking HIV

    Infected T cells, unlike some T cell lines, cannot support the production of fully infectious Δvif HIV virions, which suggests that Vif is normally required to suppress innate antiviral activity in T lymphocytes. In Nature, Malim and colleagues identify the gene responsible for this phenotype. Expression of this gene, named CEM15, establishes a nonpermissive phenotype in cells normally permissive for production of infectious Δvif HIV virions. Also, expression of Vif abrogates the antiviral activity of CEM15. Thus, this gene is likely the target for Vif function and, as a specific inhibitor of Δvif HIV infectivity, represents a form of innate antiviral resistance. Inhibiting Vif activity could represent another promising target for HIV therapy.

    Nature 14 July 2002 (doi:10.1038/nature00939)

    Mutating hypermutation

    The enzyme activation-induced deaminase (AID) is absolutely required for somatic hypermutation (SHM) of immunoglobulin (Ig) genes, the mechanism of which is unclear. In Nature, DiNoia & Neuberger provide evidence that the SHM process involves deamination of dC → dU within Ig variable genes. They hypothesize that AID generates the initial dU-dG mismatch lesion, which could be either replicated to “fix” the mutation on one strand or could be targeted by error-prone DNA repair pathways. Replication would produce transition mutations (dC → dT), but the latter process would give higher transversion frequencies (dC → dG and dA), due to the bias of repair DNA polymerases. Transversions dominate SHM-induced mutations. The authors show inhibition of uracil DNA glycosylase leads to much higher transition frequencies within mutating Ig loci from chicken DT40 cells. Thus, base excision of mismatched dU probably plays a prominent role in SHM.

    Nature 31 July 2002 (doi:10:1038/nature00981)

    Retrograde exit

    Antigen presentation by MHC class II requires retrograde transit of newly processed peptide-MHC complexes from lysosomal vesicles to the cell surface. Two reports in Nature visualize this dynamic process in live DCs. Chow et al. show that fluorescently tagged MHC class II molecules reside stably within lysosomes in immature DCs; however, upon receiving a maturation signal, rapid assembly of distinctive “retrograde transport tubules” delivers peptide-MHC class II complexes to the plasma cell membrane. Boes et al. show that DC transport of these specialized tubules is polarized to deliver their cargo to the site of interaction with antigen-specific T cells. Sustained retrograde tubule transport may maximize delivery of peptide–MHC class II complexes to the DC–T cell interface to induce T cell activation.

    Nature (in the press, 29 August 2002)

    Toll inhibitor

    TLRs sense a range of molecules that are associated with pathogens and initiate immune responses to control the spread of these pathogens. Negative feedback of TLR signaling is important in preventing excessive damage to the host due to the inflammatory response. In Cell, Kobayashi et al. show that IRAK-M negatively regulates TLR signaling in macrophages. IRAK-M−/− mice secrete higher amounts of cytokines in response to bacterial challenge, and endotoxin tolerance is impaired in these mice. IRAK-M appears to prevent dissociation of the serine-threonine kinase IRAK-4 from MyD88, an adaptor molecule that associates with the TLRs. IRAK-4 dissociation is required for binding to downstream molecules that are important in the inflammatory response. Because IRAK-M is only found in macrophages, IRAK-2, which has similar properties, may serve the same function in other cells.

    Cell 110, 191–202 (2002)

    NKG2D does it alone

    NKG2D belongs to a family of lectin-like stimulatory receptors that was originally identified on NK cells but is also expressed on macrophages and CD8+ and γδ T cells. Although recognition of its ligand by NKG2D mediates killing of the target cells, it is not clear whether NKG2D can act alone or if it is more important as a costimulatory molecule. In Immunity, Jamieson et al. generate a mAb to murine NKG2D and show that cross-linking with this antibody directly enhances cytokine secretion by NK cells and macrophages. In contrast, activation of NKG2D on CD8+ T cells does not mediate redirected lysis of Daudi target cells, suggesting that NKG2D signals differently in distinct immune cell types.

    Immunity 17, 19–29 (2002)

    CXCL12-cytokine cross-talk

    The SOCS family of proteins are important negative feedback regulators of several cytokines. The binding of Jak kinases by SOCS proteins suggests that these proteins may also regulate chemokine receptors that use the Jak-STAT signaling pathway. In the Journal of Experimental Medicine, Soriano et al. show that CXCL12 ligation enhances the expression of SOCS3, which, in turn, inhibits the activity of CXCR4. Growth hormone also induces SOCS3 expression, which results in the inhibition of cell migration in response to CXCL12. This cross-talk between cytokine and chemokine signaling may be important in understanding the complex events of development and inflammatory responses.

    J. Exp. Med. 196, 311–321 (2002)

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    Immunology highlights from the recent literature. Nat Immunol 3, 805 (2002).

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