Toll Recognition of Viral RNA Protection Against Prion Diseases

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activity. In Immunity, two groups have identi- were activated with high doses of IL-2, which Toll recognition of viral RNA fied the origins of HSCs. Cumano et al. and normally induce effector CTLs. Unambiguous Tavlan et al. separated mouse and human yolk characterization of the memory or effector CTL The innate immune response to viral infection sac (YS) and intraembryonic splanchnopleura response was based upon multiple functional involves recognition of double-stranded RNA (Sp), respectively, before circulation was estab- and phenotypic traits, including in vivo recall (dsRNA) by intracellular molecules, including lished. Cells from explanted mouse YS and Sp and homing preferences. This use of IL-15 in the dsRNA-dependent protein kinase PKR. were transferred into alymphoid mice. Sp- generating memory CTLs yields the promise of However, PKR-deficient cells can respond to derived precursors generated muti-lineage more effective vaccination strategies. the dsRNA analog poly(I:C), which suggests hematopoietic progeny in adult mice, whereas J. Clin. Invest. 108, 871–878 (2001) the existence of additional pathways for dsRNA YS cells provided short-term myeloid reconsti- recognition. In Nature, Flavell and colleagues tution. Explanted human embryonic tissues show that mammalian TLR3 recognizes were cultured in the presence of stromal cells dsRNA. TLR3-deficient mice showed reduced to promote myeloid and B cell differentiation Knotty solution for IL-17 responses to poly(I:C) and viral genomic and with mouse fetal thymus tissue to analyze dsRNA. In addition, these mice were resistant the T cell potential. Again, only human Sp Activated T cells express isoforms of the pro- to poly(I:C)-induced shock upon D-galac- cells generated muti-lineage lymphomyeloid inflammatory cytokine IL-17, which regulates tosamine sensitization and reduced production progenitors. These results show that HSCs the cartilage and extracellular matrix turnover of inflammatory cytokines. TLR3-induced originate from intraembryonic human and that characterize joint destruction in rheumatoid cytokine production after poly(I:C) recognition mouse tissue. arthritis. In the EMBO Journal, Hymowitz et was MyD88-dependent, whereas poly(I:C)- al. report the solution of the structure of human Immunity 15, 477–485 and 485–497 (2001) induced NF-κB, MAPK and dendritic cell IL-17F, which was resolved to 2.85 Å. IL-17F activation was MyD88-independent. The induces fibroblast synthesis of IL-8 and G-CSF relevance of TLR3 in the antiviral response as well as IL-6 production and proteoglycan remains to be determined. Nef is Bad shedding in human and porcine joint explants. Although the biological effects of IL-17F were Nature 413, 732–738 (2001) The HIV Nef protein is an important virulence observed at nanomolar concentrations, no bind- factor that has several functions including the ing to known IL-17A receptors was observed at enhancement of virus replication. Nef can bind higher concentrations, suggesting other mole- Protection against and activate p21-activated kinase (PAK), but its cules conferred high-affinity binding. The IL- prion diseases specific role in Nef function is unclear. In 17F structure showed a surprising similarity to Nature Medicine, Wolf et al. show that Nef- neutrophilins, such as NGF, and other cysteine © http://immunol.nature.com Group 2001 Nature Publishing As the incidence of variant Creutzfeldt-Jacob mediated PAK activation plays a role in block- knot proteins. This structural analogy leads the disease rises, the development of prophylactic ing T cell apoptosis. Nef-mediated PAK activa- way for designing therapeutic compounds that treatment will be important. However, vaccines tion was dependent on PI3K, which was also might lessen the tissue damage that ensues in may be ineffective against prion diseases bound and activated by Nef. The Nef-associated inflammatory joint diseases. because endogenous cellular prion proteins PI3K-PAK complex induced phosphorylation of EMBO J. 20, 5332–5341 (2001) (PrPcs) are poor immunogens. In Science, the pro-apoptotic Bad protein in a PKB Heppner et al. circumvent this problem by kinase–independent manner. Bad phosphory- expressing an anti-PrP immunoglobulin µ chain lation blocked T cell apoptosis induced by in PrP-deficient mice. These mice developed HIV replication. Thus, these results show a Catch and release by sustained anti-PrP titers, which were not sup- molecular function for Nef-associated PAK. The mast cell FYB pressed by introduction of the Prnp+ allele. No anti-apoptotic effects of Nef may be crucial for prion infectivity could be detected in the mice HIV replication in the host and ultimately to The Fyn-binding adaptor protein FYB, also after inoculation of the brain and spleen with disease pathogenesis. known as SLAP-130, regulates TCR signaling. scrapie prions. Resistance was not due to In the Proceedings of the National Academy of Nature Med. 7, 1217–1224 (2001) down-regulation of Prpc in the brain and spleen, Science, USA, Geng et al. report FYB express- which suggests acquired immunity was respon- ion in mast cells, where it regulates integrin- sible for protection. These results show that in mediated adhesion and mediator release upon vivo immunological protection against prion Memory CTL requirements FcεRI receptor cross-linking. Overexpression diseases is possible. of FYB led to increased adhesion to fibronectin How memory cytolytic T cells (CTLs) arise without altering integrin expression. Similarly, Science 294, 178–182 (2001) remains controversial. In the Journal of Clinical increases in wild-type FYB resulted in Investigation Manjunath and colleagues show enhanced secretory molecule release. But, memory CTL development is largely dependent unlike the potentiation of adhesion, FYB The origin of HSCs upon the cytokine mileau that antigen-activated mutants lacking the COOH-terminal SH3 CD8+ T cells encounter. Both IL-15 and low domain failed to trigger increased secretion. The origin of hematopoietic stem cells (HSCs) doses of IL-2 generated memory T cells from Thus, distinct domains in FYB link FcεRI is a matter of much controversy because both T-GFP–transgenic CD8+ cells that recognized signaling to adhesion and mediator release. the yolk sac and the intraembryonic region of the LCMV peptide GP33–41. IL-15 could also Proc. Natl Acad. Sci. USA 98, 11527–11532 (2001) vertebrate embryos show hematopoietic redirect memory CTL development in cells that

996 nature immunology • volume 2 no 11 • november 2001 • http://immunol.nature.com