This study demonstrates a unique and crucial role of plasmacytoid dendritic cells (pDCs) and pDC-derived type I interferons (IFNs) in the pathogenesis of mouse coronavirus infection. pDCs controlled the fast replicating mouse hepatitis virus (MHV) through the immediate production of type I IFNs. Recognition of MHV by pDCs was mediated via TLR7 ensuring a swift IFN-α production following encounter with this cytopathic RNA virus. Furthermore, the particular type I IFN response pattern was not restricted to the murine coronavirus, but was also found in infection with the highly cytopathic human severe acute respiratory syndrome (SARS) coronavirus. Taken together, our results suggest that rapid production of type I IFNs by pDCs is essential for the control of potentially lethal coronavirus infections.

TACE Trafficking: The cytokine tumor necrosis factor (TNF) is a major driver of inflammation and contributes to the immune pathology seen in a variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, and sepsis. Soluble TNF is produced by cleavage of its ectodomain by the ADAM family metalloprotease, TNFα-converting enzyme (TACE). However, the molecular regulation of TACE is not understood (see the Perspective by Lichtenthaler ). Adrain et al. (p. 225 ) and McIlwain et al. (p. 229 ) now show that the rhomboid family member iRhom2 interacts with TACE in macrophages and is required for its proper intracellular trafficking and activation. In the absence of iRhom2, TACE was not released from the endoplasmic reticulum, and active protease did not reach the cell surface. Because of an inability to produce TNF, iRhom2-deficient mice were more resistant to lipopolysaccharide-induced septic shock but could not adequately control a Listeria monocytogenes infection.

Erythrocyte injury such as osmotic shock, oxidative stress or energy depletion stimulates the formation of prostaglandin E₂ through activation of cyclooxygenase which in turn activates a Ca²⁺ permeable cation channel. Increasing cytosolic Ca²⁺ concentrations activate Ca²⁺ sensitive K⁺ channels leading to hyperpolarization, subsequent loss of KCl and (further) cell shrinkage. Ca²⁺ further stimulates a scramblase shifting phosphatidylserine from the inner to the outer cell membrane. The scramblase is sensitized for the effects of Ca²⁺ by ceramide which is formed by a sphingomyelinase following several stressors including osmotic shock. The sphingomyelinase is activated by platelet activating factor PAF which is released by activation of phospholipase A₂. Phosphatidylserine at the erythrocyte surface is recognised by macrophages which engulf and degrade the affected cells. Moreover, phosphatidylserine exposing erythrocytes may adhere to the vascular wall and thus interfere with microcirculation. Erythrocyte shrinkage and phosphatidylserine exposure (‘eryptosis’) mimic features of apoptosis in nucleated cells which however, involves several mechanisms lacking in erythrocytes. In kidney medulla, exposure time is usually too short to induce eryptosis despite high osmolarity. Beyond that high Cl^- concentrations inhibit the cation channel and high urea concentrations the sphingomyelinase. Eryptosis is inhibited by erythropoietin which thus extends the life span of circulating erythrocytes. Several conditions trigger premature eryptosis thus favouring the development of anemia. On the other hand, eryptosis may be a mechanism of defective erythrocytes to escape hemolysis. Beyond their significance for erythrocyte survival and death the mechanisms involved in ‘eryptosis’ may similarly contribute to apoptosis of nucleated cells.

Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3 ^−/− , E4BP4 ^−/− ) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.