More than one STAT required

Activation of the transcription factor STAT6 is critical to TH2 differentiation, whereas activation of STAT3 is required for the differentiation of TH17 cells and follicular helper T cells. In Immunity, Kaplan and colleagues show that STAT3 is required for TH2 cytokine production and transcription factor expression. STAT3 is phosphorylated during TH2 differentiation, and STAT3-deficient T cells have diminished production of IL-4, IL-5 and IL-13. STAT3 directly binds to the Gata3, Maf, Batf and Irf4 loci, where it limits repressive chromatin modifications and allows the binding of STAT6 and activation of these genes. In the absence of STAT3, binding of STAT6 to these loci is either undetectable or greatly diminished. Loss of STAT3 is protective against the development of TH2 cell–mediated inflammatory diseases in models of pulmonary and skin inflammation. Thus, TH2 differentiation requires integration of multiple STAT protein signals. IV

Immunity (6 January 2011) doi:10.1016/j.immuni.2010.12.013

Redox-sensitive killing

Epithelial cells release β-defensins that contribute to innate antimicrobial protection at tissue barriers. Although β-defensin-1 is the most abundant, its is much less potent than β-defensin-3. In Nature, Schroeder et al. show that the antimicrobial activity of β-defensin-1 is governed by its redox status. In aerobic environments, β-defensin-1 adopts a rigid structure with three intramolecular disulfide bonds, which is correlated with low antimicrobial activity. Reduction of these disulfide bonds with either dithiothreitol or thioredoxin plus NADPH leads to a more flexible molecule with potent killing activity toward Gram-positive bacteria and Candida fungi. The C-terminal heptapeptide GKAKCCK also has antimicrobial activity. In situ immunostaining demonstrates colocalization of β-defensin-1 and thioredoxin in human colonic mucosa and skin epidermis. Thus, the physiological redox environment regulates host innate defense mediated by β-defensin-1. LAD

Nature (27 January 2011) doi:10.1038/nature09674

Stem cell maintenance

Whether common or distinct regulatory mechanisms are used to control the specification, formation and maintenance of hematopoietic stem cells (HSCs) remains unclear. In Genes & Development, Toudi et al. show that the Ets family transcription factor ERG is a critical regulator of fetal HSC maintenance. Lack of functional ERG in mutant embryos does not affect the specification or generation of hematopoietic progenitor cells. Using chimeras, the authors prove that Erg-deficient HSCs can generate multiple hematopoietic lineages and seed secondary hematopoietic organs. However, lack of ERG leads to HSC exhaustion, probably through an effect on progenitor self-renewal during fetal life. In fetal liver progenitors, ERG is a direct positive regulator of the activity of Gata2 and Runx1. These results suggest that Runx1 and GATA-2 not only are essential regulators of hematopoietic specification but also are required later in development to control HSC self-renewal. IV

Genes Dev. (18 January 2011) doi:10.1101/gad.2009211

A peaceful brain with miRNA

MicroRNAs have emerged as critical regulators of diverse physiological processes, including many pertaining to immune function. In Nature Medicine, Weiner and colleagues demonstrate a key role for miR-124 in down-modulating microglia activation. This microRNA is known to have the highest expression among brain-specific microRNAs, and this study further demonstrates its presence in resting microglia. Induction of experimental autoimmune encephalitis results in microglial activation and concomitantly less miR-124. Similarly, activation of microglia ex vivo results in lower miR-124 expression. Macrophages are closely related to microglia but do not express miR-124; however, enforcing its expression causes macrophages to assume a resting microglia–like phenotype. Moreveor, miR-124 acts via inhibition of the transcription factor C/EBP-α and its downstream target PU.1; the latter is required for monocyte differentiation. Therefore, miR-124 is a potent regulator of microglial quiescence and thus has an important function in controlling inflammation in the central nervous system. ZF

Nat. Med. 17, 64–70 (2011)

NKT cells recognize self

NKT cells typically recognize glycolipid antigens presented via the nonclassical MHC molecule CD1d, but the presentation of more classical exogenous peptides has been documented. In the Journal of Clinical Investigation, Issazadeh-Navikas and colleagues now report the recognition of a classical endogenous peptide by NKT cells. They show that a peptide derived from mouse collagen II is able to activate NKT cells in a polyclonal TCR– and costimulation-dependent manner. Notably, this peptide is not presented by MHC class I or class II and is thus unable to stimulate conventional T cells. Activation results in NKT cell expression of a range of cytokines, including IL-4, IFN-γ, TGF-β1 and IL-17. Activated NKT cells are also strongly suppressive in vitro and kill T cell targets via interactions of the cell surface receptor Fas with its ligand, FasL. Finally, immunization with the mouse collagen II peptide is protective in several in vivo models of autoimmunity or allergic airway hypersensitivity. This study provides further evidence that NKT cells are important in the maintenance of self-tolerance. ZF

J. Clin. Invest. 121, 249–264 (2011)

Viral inflammasome inhibitor

Inflammasomes can be activated by various environmental or microbial triggers. In Science, Gregory et al. identify Orf63, a homolog of the inflammasome NLRP1 encoded by Kaposi's sarcoma herpesvirus (KSHV) that inhibits host inflammasome activation. KSHV Orf63 is similar to the leucine-rich repeat domain of NLRP1, but lacks homology to the pyrin and CARD domains necessary for caspase-1 activation. Orf63 blocks the association of NLRP1 with its substrate, the precursor to caspase-1. Cells expressing Orf63 generate less mature IL-1β and IL-18 and are more resistant to NLRP1-dependent pyroptosis. Knockdown of Orf63 expression in latently infected KSHV+ primary effusion lymphoma cells results in less viral proliferation after reactivation and lessens viral infectivity of naive cells in vitro. Thus, KSHV uses a dominant negative inflammasome homolog to inhibit host antiviral defenses. LAD

Science 331, 330–334 (2011)

Written by Laurie A. Dempsey, Zoltan Fehervari & Ioana Visan