Letters in 2009

The Wnt pathway has a central role in stem cell regulation. Gattinoni et al. now show that activation of the Wnt signaling cascade in naive CD8⁺ T cells blocks their differentiation into effector T cells and triggers instead a memory stem cell–like phenotype. These T memory stem cells show enhanced antitumor efficacy in mice compared with other T cell subsets, arguing for their further evaluation in adoptive immunotherapies (pages 731–732).

Studies in macaques have shown that neutralizing antibodies can offer robust protection from infection with a simian counterpart of HIV, yet these studies have also suggested that high concentrations of antibodies are required for efficient protection. Unfortunately, it's not generally thought to be feasible to elicit such high neutralizing antibody titers by vaccination. Dennis Burton and his colleagues now show that lower concentrations of antibodies can offer protection to macaques if a repeated low-dose challenge model is used—a model that may better recapitulate the acquisition of infection in humans.

Pain is one of the many debilitating side effects of cancer. Now, Rohini Kuner and her colleagues show that blocking hematopoietic colony-stimulating factor signaling on neurons can inhibit pain caused by bone cancer.

Although type I interferons such as interferon-α are well known to protect against viral infection, they may have other physiological effects in the uninfected state. Taku Sato et al. now show that type I interferon signaling in hematopoietic stem cells promotes their proliferation and impairs their ability to reconstitute the hematopoietic system (pages 696–700).

In a new report, Satoru Noguchi and his colleagues have shown that oral administration of various sialic acid compounds helps improve the behavior of skeletal muscles in a mouse model of a severely debilitating human muscle disease—one with no current treatment option. Given the simplicity of their approach, it is possible these findings could have immediate clinical impact.

Hypoxia-triggered neovascularization occurs in many types of disease. Endothelial cells must be able to cope with hypoxic stress, which in other cell types can induce a DNA repair response and inhibit replication. Matina Economopoulou et al. now show that hypoxia induces the generation of a hallmark of the DNA repair response, phosphorylated histone H2AX, in proliferating endothelial cells and that H2AX function is required for neovascularization under hypoxic or ischemic conditions in vivopages 491–493..

Primary prostate cancer is genomically highly heterogeneous and is thought to derive from multiple independent clones of cancer cells. Using high-resolution genomic analyses, Bova et al. now show that, in contrast to primary tumors, metastases are monoclonal, originating from a single cancer cell. These findings call into question current views of the origins of primary prostate cancer and suggest that the genomic profile of prostate cancer metastases should inform therapeutic decisions.

Granulocyte colony-stimulating factor (G-CSF) is used to accelerate neutrophil engraftment in bone marrow transplant (BMT) recipients to reduce bacterial infections but may also enhance the risk of graft-versus-host disease (GVHD). Morris et al. now show that total body irradiation increases the expression of the G-CSF receptor on recipient dendritic cells, resulting in the activation of donor natural killer T cells and enhanced GVHD when G-CSF is administered shortly after BMT (pages 363–364).

One way to reduce obesity is to alter fat absorption from the diet. Here Robert Farese, Jr. and his colleagues identify MGAT2 as a potential therapeutic target for doing so. The enzyme is mostly expressed in the gut of humans and mice, and its genetic deletion in mice results in slower kinetics of fat absorption—more of the fat is burned and less is stored, offering protection from diet-induced obesity.

Hypoxia promotes tumor growth by stimulating angiogenesis, glycolysis, resistance to apoptosis and cell invasion. Wang et al. now report that hypoxia also increases the duration of growth factor signaling in tumor cells. They show that hypoxia-inducible factor downregulates the expression of an effector of early endosome fusion, slowing the endocytic recycling of epidermal growth factor receptor and thereby extending its activation and potential to enhance tumor cell proliferation and survival (pages 246–247).

In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation (pages 249–250, 300–305 and 313–318).

In this issue, three reports show that Kindlin-3 is crucial for activation of multiple classes of integrins in several types of hematopoietic cells. In mice, Kindlin-3 was previously shown to be important for platelet activation and blood clotting, and Moser et al. now show its importance in leukocytes for adhesion to the endothelium. In humans, Svensson et al. and Malinin et al. show that mutation of the gene encoding Kindlin-3 is associated with a disease syndrome involving severe bleeding, infection and osteopetrosis, which Malinin et al. showed could be corrected by bone marrow transplantation (pages 249–250, 300–305 and 306–312).

Kindlin-3 interacts with β₁ and β₃ integrins on platelets, and Kindlin-3–deficient mice have defects in platelet activation and blood clotting. Moser et al. now show that these mice also have defects in β₂ integrin activation on leukocytes, leading to severely compromised leukocyte adhesion to the endothelium. The combined platelet and leukocyte defects of these mice resemble those seen in individuals with the leukocyte adhesion deficiency syndrome LAD-III. Other papers in this issue by Malinin et al. and Svensson et al. provide evidence that KINDLIN-3 dysfunction does indeed underlie this type of human disease syndrome (pages 249–250, 306–312 and 313–318).

Issue:Vaccines that induce T cell responses to simian immunodeficiency virus are able to reduce virus load in infected macaques. Such vaccines typically induce central memory T cells that must expand before gaining full antiviral functions. Picker and his colleagues show that a new replicating anti-SIV vaccine, based on the persistently infecting cytomegalovirus, which preferentially induces effector memory T cells in mucosal tissues, can reduce the likelihood that the macaques become infected in the first place (pages 244–246).

Mark Tuszynski and his colleagues show that brain-derived neurotrophic factor is neuroprotective and can improve cognition in rodent and primate models of Alzheimer's disease.

Increased calcium levels in dystrophic muscle have damaging consequences. In this report, Bellinger et al. show that nitrosylation of the ryanodine receptor calcium channel, leading to calcium leak through the channel, is an underlying cause of increased calcium levels in the muscle of dystrophic mdx mice. Treatment of the mice with a compound that inhibits calcium leak increases their muscle function and physical activity, pointing to a potential new treatment for muscular dystrophy (pages 243–244).

Does Mycobacterium tuberculosis replicate in vivo, or does it persist in the host in a nonreplicating latent state? David Sherman and his colleagues have developed a technique to answer this question in mice and find that the mycobacteria do replicate in vivo. It is unknown whether these findings will hold true in other animals, particularly nonhuman primates, but this technique could be applied to study the in vivo replication of other persistent pathogens responsible for chronic infections.

TNF is a key pathogenic cytokine in sepsis. Oberdan Leo and colleagues show that production of TNF during sepsis is regulated by the coenzyme NAD and that inhibition of the enzyme NAMPT, which generates NAD from nicotinamide, can improve survival during sepsis in mice. NAD seems to act via sirtuin-6 to increase the translation of TNF.

Ethylmalonic encephalopathy is an autosomal recessive developmental disorder that is characterized by chronic diarrhea and multiple neurological deficits. It is associated with loss-of-function mutations in the ETHE1 gene. Now, Massimo Zeviani and his colleagues report that ETHE1 is a dioxygenase that is responsible for breaking down toxic sulfide in a variety of organs.

The chemokines CCL5 and CXCL4 promote monocyte recruitment to atherosclerotic plaques. Recent findings in vitro have shown that heteromerization of CCL5 and CXCL4 increases their potency in stimulating monocyte adhesion and chemotaxis. Koenen et al. now show that this heteromerization has functional consequences in vivo. Treatment of atherosclerotic mice with a cyclic peptide that specifically disrupts the CCL5-CXCL4 interaction inhibited monocyte recruitment to atherosclerotic plaques. Moreover, selective inhibition of heteromer formation may offer therapeutic advantages compared to complete blockade of chemokine function.