A potent antigen-specific T cell response to HIV infection can contribute to the control of viral replication and is therefore beneficial to the host. However, HIV-mediated increases in generalized T cell activation also appear to accelerate both viral replication and CD4+ T cell depletion. A new study in the JCI attempts to experimentally distinguish the beneficial versus harmful aspects of this immune response.
Steven G. Deeks, Bruce D. Walker
Neurotrophic growth factors, including nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF), have well-established roles in promoting the innervation of target tissues, yet little is known about how the temporal and organ-specific expression of these factors is regulated. A new study reveals that NGF is a direct target of the well-characterized peptide factor endothelin-1 (ET-1), and that ET-1–induced NGF expression is required for sympathetic innervation of the developing heart. These results, and recent studies implicating GDNF and ET-3 in the patterning of the enteric nervous system, suggest that specific pairing of endothelins and neurotrophic factors may be used in distinct target organs to coordinate neuronal migration, differentiation, and survival.
Barbara L. Hempstead
Langerhans cells (LCs) represent a unique DC subset populating the outermost body surface, i.e., the epidermis. Although CD1a and langerin (CD207) are used as specific markers to distinguish LCs from other DC subsets, their immunological functions have remained mostly unknown. A new paper (see the related article beginning on page 701) demonstrates that LCs utilize these markers to induce cellular immune responses to Mycobacterium leprae: CD1a mediates the presentation of nonpeptide antigens to T cells, while langerin facilitates uptake of microbial fragments and perhaps their delivery to a specialized subcellular compartment.
Norikatsu Mizumoto, Akira Takashima
When facing an immune response, viruses can either attempt to elude them or confront them. A new report demonstrates that a lymphocytic choriomeningitis virus (LCMV) strain can suppress immune responses by targeting both development and activation of DCs. Ironically, type I IFN released in response to LCMV infection contributes to the blockade of DC development. The discovery of these immunosuppressive mechanisms provides new perspectives for the therapy of chronic infections associated with immunosuppression.
Marco Colonna
Computer simulations are potentially effective approaches to unraveling the causes of lethal heart rhythm disorders. In this issue of the JCI, Xie et al. have embedded a well-characterized dynamic mechanism for arrhythmia development in an anatomically realistic computer model of the heart. Their demonstration that this simple mechanism governs the behavior of the complex model may provide a new target for strategies to prevent sudden death.
Robert F. Gilmour Jr.
Despite the initial excitement over cancer vaccines, the clinical effectiveness of immunotherapy has been disappointing. The suppressive milieu present within established tumors inhibits effective immune responses, although new strategies are emerging to manipulate the local tumor microenvironment and shift the balance back to a proinflammatory environment, promote DC activation, and enhance tumor immunity .
Howard L. Kaufman, Mary L. Disis
Ataxia is a lethal neurological disease characterized by incoordination, postural abnormalities, difficulties with gait, and problems with clarity of speech. The etiology of ataxia is divided equally between hereditary and sporadic forms. Regardless of cause, the cerebellar cortex is often a target in ataxia. Thus, how a disruption in cerebellar cortex might lead to ataxia is of considerable interest. A report in this issue of the JCI links ataxia to enhanced hyperexcitability of neurons in the deep cerebellar nuclei.
Harry T. Orr
Eosinophils accumulate in high numbers in the lungs of asthmatic patients. These cells have the ability to induce tissue damage, a capacity that relates to their traditional role in host defense against parasitic worms. On the other hand, eosinophils produce growth factors associated with tissue repair and remodeling, notably TGF-β1. The relationship of these activities to lung dysfunction in asthma is highly controversial, but recent observations in humans and in animal models add spice to the debate .
Timothy J. Williams
Circulating levels of HDL cholesterol are inversely related to the risk of atherosclerosis, and therapeutic increases in HDL reduce the incidence of cardiovascular events. A new study shows that HDL-associated lysophospholipids stimulate the production of the potent antiatherogenic signaling molecule NO by the vascular endothelium.
Philip W. Shaul, Chieko Mineo
Protein methylation at the C-terminus of mammalian isoprenylated proteins has been implicated in membrane attachment, protein-protein interactions, and protein stability. A new paper describes surprising results: in the absence of methylation some target proteins have increased stability, whereas others have decreased stability. The decreased stability of the RhoA protein is correlated with an increased resistance to Ras-dependent transformation and suggests the basis for the development of a new approach to antitumor therapy .
Steven Clarke, Fuyuhiko Tamanoi
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