Peyer's patch pDCs

Peyer's patches are sites in the small intestine that contain specialized cells, including plasmacytoid DCs (pDCs), that influence gut-associated immune responses. In Journal of Immunology, Kelsall and colleagues evaluate Peyer's patch pDCs for the production of type I interferon (IFN-α/β) after stimulation with either influenza virus or CpG-containing oligonucleotide. Most pDCs are known to secrete large amounts of type I interferon after stimulation with these TLR9 ligands. The authors find that Peyer's patch pDCs, in contrast, do not produce substantial IFN-α/β after being stimulated with either TLR9 ligand. Mucosa-associated interleukin 10, transforming growth factor-β and prostaglandin E2 are associated with suppression of pDC IFN-α/β expression. Transforming growth factor-β functions early to prevent the transcription of IFN-β mRNA, whereas interleukin 10 probably prevents autocrine IFN-α/β signaling. These data explain how Peyer's patch pDCs remain quiescent in the face of copious potential TLR9 ligands in the gut. DCB

J. Immunol. 179, 2690–2694 (2007)

The terminator

The transcription factor NF-κB signaling pathway is highly regulated to ensure transient expression of inflammatory mediators. In the EMBO Journal, Harhaj and colleagues show that the regulatory molecule TAX1BP1 is needed to turn off both the NF-κB and Jnk kinase signaling pathways in response to stimulation by lipopolysaccharide and the proinflammatory cytokines TNF and interleukin 1. TAX1BP1-null mice die in utero. Fibroblasts derived from deficient embryos show heightened activity of the kinases IKK and Jnk and sustained NF-κB nuclear DNA-binding activity, which results from a failure to accumulate the inhibitor IκBα after stimulation. TAX1BP1 is needed to recruit the deubiquitinating enzyme A20 to ubiquitin-activated adaptor proteins TRAF6 and RIP1. These findings place TAX1BP1 'upstream' of A20, where it is essential in leading to the termination of proinflammatory signaling cascades. LAD

EMBO J. (16 Aug 2007) doi:10.1038/sj.emboj.7601823

Antiviral self RNA

Mice lacking the interferon-inducible 2′,5′-oligoadenylate (2-5A)–dependent endoribonuclease RNase L have impaired antiviral immunity. In Nature, Silverman and colleagues elucidate the precise molecular mechanism by which RNase L contributes to innate cellular defenses. The oligoadenylate 2-5A induces production of interferon-β (IFN-β) in mouse embryonic fibroblasts in a way that is dependent on catalytically active RNase L as well as the RNA helicases RIG-I and Mda5 and the adaptor protein IPS-1. RNA cleavage products generated by in vitro treatment of cellular RNA with RNase L trigger the formation of multimers of RIG-I and the transcription factor IRF3 and elicit IFN-β from wild-type cells but not cells deficient in RIG-I, Mda5 or IPS-1. RNase L–deficient mice infected with RNA viruses have less serum IFN-β than their wild-type counterparts do. These findings indicate that RNase L, in addition to its function in cleaving viral RNA in infected cells, propagates a more global antiviral state in vivo. CB

Nature 448, 816–820 (2007)

PI(3)K in NK cells

The influence of specific phosphatidylinositol-3-OH kinase (PI(3)K) proteins on natural killer (NK) cell development and function remains unclear. In Immunity, Colonna and colleagues show that the PI(3)K catalytic subunits p110γ and p110δ work synergistically yet distinctly to control NK cell differentiation and activity. NK cells in mice lacking both p110δ and p110γ are fewer in number and have an immature surface phenotype and impaired cytotoxicity; NK cell differentiation proceeds relatively normally in the absence of either p110δ or p110γ. However, elaboration of IFN-γ dependent on ITAM-containing receptors is impaired in p110γ-deficient NK cells, whereas cytokine-induced activation of p38 kinase and production of IFN-γ are higher in p110δ-deficient NK cells. Inhibition of the kinase Erk or the lipoxygenase pathway suppresses the production of IFN-γ by NK cells induced by ITAM-containing receptors, suggesting involvement of G protein–coupled receptor signaling. Nevertheless, more study is needed to unravel the web of NK cell signaling pathways that use p110γ and/or p110δ. CB

Immunity 27, 214–227 (2007)

Genetics of HIV resistance

There is considerable variation in viral load set point and onset of clinical disease among people infected with human immunodeficiency virus 1 (HIV-1). In Science, Fellay et al. identify allelic single-nucleotide polymorphisms (SNPs) associated with differences in these two parameters in cohorts of patients with AIDS. One SNP in HCP5 is located near HLA-B in an endogenous retroviral element. Another is in the 5′ regulatory control region of HLA-C. People with this SNP variant have an inverse correlation of HLA-C expression and retroviral load, suggesting HLA-C presentation offers some protection against HIV. Several SNPs associated with slower disease progression are located near ZNRD1, which encodes a component of RNA polymerase I. Future work will help delineate how these variant SNPs help to protect hosts against HIV. LAD

Science 317, 944–947 (2007)

TLR4 tackles tumors

Successful radiation and/or chemotherapeutic treatment of tumors is thought to rely on direct elimination of tumor cells with little involvement of the immune system. In Nature Medicine, Zitvogel and colleagues demonstrate instead that such treatments require innate and adaptive immune responses stimulated by a treatment-dependent, tumor cell–released factor and Toll-like receptor 4 (TLR4). In vitro and in vivo experiments with irradiated or chemotherapeutically treated (dying) tumor cells show that dendritic cell (DC) cross-presentation of antigen to T cells requires TLR4 and the TLR adaptor protein MyD88. However, TLR4 is not required for DC-dependent T cell responses to soluble antigen. Irradiation releases HMGB1, a purported TLR4 ligand, from tumor cells. Inhibition of HMGB1 expression in dying cells by RNA-mediated interference or treatment of DCs with TLR4-Fc prevents cross-presentation to T cells. Patients with breast cancer who have a homozygous mutation in TLR4 show statistically higher metastasis 5 years after surgery. These data indicate that stimulation of TLR4 by HMGB1 'licenses' DCs for antigen presentation of dying tumor cells. DCB

Nat. Med. (19 August 2007) doi:10.1038/nm1622

Written by Christine Borowski, Douglas C. Braaten and Laurie A. Dempsey