News & Views in 2012

During sterile inflammation, emigrating leukocytes sequentially engage subsets of pericytes associated with blood vessels and acquire adhesive, migratory and survival signals.

Feedback inhibition by interferon-γ blocks the NLRP3 inflammasome by triggering inducible nitric oxide synthase (iNOS), and the resulting nitric oxide (NO) thio-nitrosylates NLRP3, shutting it down. This prevents excessive immunopathology during chronic infection with Mycobacterium tuberculosis.

The mechanisms by which cells detect and fight foreign organisms is crucial for the host defense against infection. The sensing of cytosolic DNA is pivotal in this process, is kept in check by the exonuclease Trex1 and has been linked to lysosomal biogenesis via the transcription factor TFEB in an interferon-independent manner.

Psoriasis is associated with the T_H17 subset of helper T cells. Dysregulation of interleukin 17 (IL-17) signaling leads to enhanced T_H17 differentiation, more production of IL-22 and IL-22-dependent skin inflammation.

Diseased host cells are eliminated more effectively when natural killer cells grow up in the presence of classical major histocompatibility complex (MHC) class I molecules. The nonclassical MHC class I molecule H2-M3 can exert an analogous effect.

Interleukin 2 (IL-2) and IL-15 use receptors with the same signaling subunits. New structural data show that the signaling complexes they form are topologically nearly identical, which suggests that other factors are responsible for the distinct signaling properties of these complexes.

Mathematical modeling shows that two members of the NF-κB family of transcription factors, RelB and p50, form heterodimers and participate in the canonical NF-κB pathway in dendritic cells.

Autoinflammation and immunodeficiency are rare in humans, but the rate of discovery of these conditions has increased. Three patients have now been characterized in whom deficiency in HOIL-1, a component of the LUBAC complex, leads to these conditions.

Bacterial cyclic dinucleotides are recognized by the innate immune system, and this leads to the induction of type I interferons. The mammalian helicase DDX41 directly binds cyclic dinucleotides and mediates the signaling pathway to the induction of type I interferons.

The deubiquitinating enzyme USP25 restricts ubiquitination of the adaptors TRAF5 and TRAF6 and signaling via interleukin 17 and thus joins several ubiquitin-modifying enzymes already known to regulate this biomedically important pathway.

Limiting immune responses is critical for protecting the host from harm. The p110δ isoform of the kinase PI(3)K acts as a balance between pro- and anti-inflammatory TLR4 signaling in dendritic cells.

The kinase TBK1 participates in signaling pathways that induce antimicrobial responses. TBK1 is also necessary for the suppression of excessive production of immunoglobulin A by accelerating destruction of the kinase NIK.

A fundamental mystery of the biology of germinal center B cells is why it seems that these rapidly dividing B cells lack expression of c-Myc, a transcriptional regulator intimately linked to cell metabolism and proliferation. This mystery has now been resolved.

The secretion of cytokines by helper T cells is affected by the cytokine environment and by costimulatory signals. Engagement of the receptor OX40 on T cells increases expression of the transcription factor TRAF6, activates the alternative transcription factor NF-κB pathway and induces the production of interleukin 9.

The axis of lymphotoxin and its receptor LTβR influences the composition of the host gut microbiome, leading to excessive weight gain in hosts fed a high-fat diet.

Foxp3 protein complexes orchestrate the transcriptional network of regulatory T cells. The Foxp3 interactome is now identified and may act as a genetic switch that controls the differentiation of regulatory T cells.

The activation of T cells requires the entry of calcium ions through the plasma membrane. A study now identifies a voltage-gated sodium channel as being essential for the sustained entry of calcium needed for the developmental process of positive selection.

The characteristics of the tumor microenvironment vary widely. New work shows that after tumor-associated expression of the receptor TIM-3 by dendritic cells, TIM-3 inhibits the antitumor efficacy of DNA vaccines and chemotherapy by binding to the damage-associated molecular pattern molecule, HMGB1.

The mechanism by which γδ T cells are triggered to respond to stress elicited by infection or malignancy has remained a mystery. New data identify endothelial protein C receptor as a stress ligand for γδ T cells that is induced by cytomegalovirus infection.

Structural studies identify considerable differences in the recognition of CD1d-lipid complexes by the TCRs of type II and type I (invariant) natural killer T cells.