EDITOR'S PICK
Timing is everything when using IL-7 to boost antiviral immunity
CD8+ T cells are an important component of antiviral immune responses. Much research effort is being invested in identifying new ways to boost antiviral immune responses in individuals with chronic viral infections (such as those infected with HIV and hepatitis C virus) and to boost the efficacy of vaccines designed to target these viruses. The use of the soluble factor IL-7, which is known to be important in the generation and maintenance of memory CD8+ T cells, has proven attractive. However, new data, generated in mice by M. Suresh and colleagues at the University of Wisconsin–Madison, have indicated that the timing of IL-7 treatment is important in determining how effective it is at enhancing antiviral immunity.
In the study, IL-7 was shown to enhance the number and function of memory CD8+ T cells only if it was administered during the contraction phase of the immune response mounted after mice were infected with either lymphocytic choriomeningitis virus or vaccinia virus, or were administered a DNA vaccine. Importantly, CD8+ T cells from IL-7–treated mice exhibited improved viral control. These data have clinical implications for the use of IL-7 as an immunotherapeutic agent both to bolster vaccine-induced CD8+ T cell memory and to boost the immune response of individuals with a chronic viral infection.
TITLE: Effects of IL-7 on memory CD8+ T cell homeostasis are influenced by the timing of therapy in mice
AUTHOR CONTACT:
M. Suresh
University of Wisconsin–Madison, Madison, Wisconsin, USA.
Phone: (608) 265-9791; Fax: (608) 263-0438; E-mail: sureshm@svm.vetmed.wisc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32020
CARDIOLOGY
Precursor cells may provide clues to cardiac development
Progenitor cells have the ability to develop into various cell types by a process known as differentiation. In a new study, John Gearhart and colleagues at Johns Hopkins Medical Institutions, Baltimore, used heart progenitor cells [cardiac progenitor cells (CPCs)] isolated from mouse embryonic stem–cell cultures to identify genes that had not previously been known to function in cardiac development.
Although undifferentiated CPCs expressed proteins exclusive to stem cells or mesodermal cells, differentiated CPCs expressed markers for three different cell fates — cardiomyocytes, vascular smooth muscle cells, and endothelial cells. The temporal regulation of genes in the cultured CPCs was similar to that found in the developing mouse heart, and allowed the identification of a number of genes not previously known to function in cardiac development. These results led the authors to conclude that differentiation of CPCs derived from mouse embryonic stem cell–cultures might provide a useful model for studying heart development.
TITLE: Mouse ES cell–derived cardiac precursor cells are multipotent and facilitate identification of novel cardiac genes
AUTHOR CONTACT:
John D. Gearhart
Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Phone: (410) 614-3444; Fax: (410) 955-7427; E-mail: gearhart@jhmi.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33942
DERMATOLOGY
Ouch, Smad hurts! Smad7 may inhibit wound healing
A vital step in the process of wound healing is reepithelialization, the growth of epithelial tissue over a wound site. Growth factors (including TGF-beta-1) and adhesion molecules (including integrins) help regulate wound healing, but how these molecules coordinate to regulate the process has not been well determined. A new study by Kairbaan Hodivala-Dilke and colleagues, at Queen Mary’s School of Medicine and Dentistry, London, has identified one level of coordination, and this revealed new roles for the integrin alpha-3-beta-1 and the TGF-beta-1 inhibitor Smad7 in reepithelialization.
Mice deficient in the alpha-3 subunit of alpha-3-beta-1 exhibited impaired reepithelialization following skin wounding, and this was associated with repression of TGF-beta-1–mediated responses and increased Smad7 activity. Blocking Smad7 activity in these mice restored reepithelialization to levels found in normal mice. These results indicated that alpha-3-beta-1 mediates wound healing indirectly through Smad7 inhibition, and led the authors to suggest that Smad7 may be a useful target for the development of new approaches to treating cutaneous wounds.
TITLE: alpha-3-beta-1 integrin–controlled Smad7 regulates reepithelialization during wound healing in mice
AUTHOR CONTACT:
Kairbaan M. Hodivala-Dilke
Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, United Kingdom.
Phone: 44-207-014-0406; Fax: 44-207-014-0401; E-mail: Kairbaan.Hodivala-Dilke@cancer.org.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33538
NEUROBIOLOGY
Managing chronic pain
Opioids, such as morphine, are effective and widely used drugs for the control of pain. However, tolerance to opioids can develop with repeated administration (that is, higher and higher doses of the drug are required to achieve the same level of pain relief). Nonetheless, there is some evidence to suggest that tolerance to opiods does not develop when they are used to treat individuals with diseases that are accompanied by inflammation. Support for this hypothesis has now been provided by Christian Zöllner and colleagues from Charité–Universitätsmedizin Berlin, Germany, who found that peripheral tolerance to morphine did not develop in the chronically inflamed paws of rats. Furthermore, blocking the action of endogenous opioid compounds in the inflamed tissue enabled tolerance to morphine to develop. These data indicated that under conditions of chronic pain, endogenous opioid compounds prevent morphine from causing tolerance, inferring that the use of peripherally acting opioids for the prolonged treatment of inflammatory diseases such as chronic arthritis, inflammatory neuropathy, and cancer is not necessarily accompanied by opioid tolerance.
TITLE: Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain
AUTHOR CONTACT:
Christian Zöllner
Charité — Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Phone: 49-30-8445-3678; Fax: 49-30-8445-4469; E-mail: christian.zoellner@charite.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25911
VIROLOGY
Genetic differences translated into functional diversity
New data generated by Barbara Rehermann and colleagues at the National Institutes of Health, Bethesda, using an in vitro model of infection with influenza A virus (IAV), has provided a functional explanation for the results of genetic studies that indicate certain KIR/HLA compound genotypes influence the outcome of viral infections.
In the study, the fraction of the subset of immune cells known as NK cells that is inhibited by HLA-C was larger and responded more rapidly (as determined by IFN-gamma secretion and CD107a degranulation assays) in individuals with two HLA-C1 genes than in individuals with two HLA-C2 genes. These results provide functional evidence that the responsiveness of NK cells differs depending on KIR/HLA genotype and provides insight into the distinct innate immune response generated by different individuals to viral infections such as IAV.
TITLE: Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses
AUTHOR CONTACT:
Barbara Rehermann
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 402-7144; Fax: (301) 402-0491; E-mail: rehermann@nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32400
IMMUNOLOGY
New way to assess the importance of cross-reactive CD8+ T cells
CD8+ T cells are an important component of the antiviral immune response and they respond to peptides derived from viral proteins. Although it was originally thought that each CD8+ T cell recognized only one peptide, it is now known that these cells can react to several different peptides (i.e., they are cross-reactive). To determine the biological importance of cross-reactivity it is important to determine the directionality and quality of the cross-reactions. A team of researchers at the University of Oxford and Harvard Medical School has now developed a new tool to investigate this in humans expressing the HLA-A2 MHC class I protein.
In the study, a new mutant form of HLA-A2 that binds CD8 more strongly than normal HLA-A2 was used to generate peptide–MHC class I complexes (pMHCs). Using these pMHCs it was shown that CD8+ T cells that react to both a hepatitis C virus peptide (HCV-NS3) and a peptide derived from the influenza neuraminidase protein (Flu-NA) cross-react only very weakly. Furthermore, CD8+ T cells that react to Flu-NA were only detected in individuals infected with hepatitis C virus, indicating that reactivity toward the Flu-NA peptide occurs mainly after infection with hepatitis C virus. Together, these data led the authors to suggest that the biological relevance of the cross-reactivity that they investigated is likely to be low.
TITLE: Defining the directionality and quality of influenza virus–specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus
AUTHOR CONTACT:
Paul Klenerman
University of Oxford, Oxford, United Kingdom.
Phone: 44-1865-281885; Fax: 44-1865-281236; E-mail: paul.klenerman@ndm.ox.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33082
HEMATOLOGY
Linking it all together: a Lyn, Hck, SHIP signaling pathway susceptible to myeloproliferative disease
Myeloproliferative diseases, including chronic myelogenous leukemia, are characterized by an overproduction of cells by the bone marrow. In a new study, Toshiaki Kawakami and colleagues, at the La Jolla Institute for Allergy and Immunology, have revealed new details about a signaling pathway that leads to myeloproliferation and lung disease in mice. Similar to previous observations in mice lacking the protein SHIP, the authors observed that mice deficient in the proteins Lyn and Hck overproduced blood stem cells (HSCs) and developed a myeloproliferative disease that was accompanied by inflammation of the lungs, characterized by the accumulation of immune cells known as M2 macrophages. Expression of SHIP in HSCs lacking Lyn and Hck restored normal blood cell development and prevented myeloproliferation, delineating a signaling pathway controlled by Lyn/Hck/SHIP that regulates HSC differentiation and M2 macrophage programming, disruption of which can lead to myeloproliferative disease.
TITLE: Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5
AUTHOR CONTACT:
Toshiaki Kawakami
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: (858) 752-6814; Fax: (858) 752-6986; E-mail: toshi@liai.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34013
HEMATOLOGY
Marking the transition from myeloproliferative disorder to acute myeloid leukemia
Once myeloproliferative disorders (MPDs) progress to acute myeloid leukemia (AML) they become hard to treat and prognosis is poor. Therefore, characterizing molecular markers of this transition is important for determining prognosis and identifying potential targets for therapeutic intervention. New data generated in mice by Elizabeth Eklund and colleagues at Northwestern University Feinberg School of Medicine, Chicago, have provided new insight into one mechanism by which an MPD can progress to AML.
Mice lacking the protein ICSBP develop an MPD that progresses to AML over time, suggesting that the ICSBP deficiency alone is not sufficient for AML progression and that other events must occur for this to happen. In this study, mice transplanted with bone marrow cells in which only one of the two genes that direct production of ICSBP was functional and that expressed constitutively active SHP2 developed an MPD that rapidly progressed to AML. These data suggest that genetic mutations affecting ICSBP expression can synergize with those causing SHP2 to be constitutively activated to facilitate MPD progression to AML. The clinical importance of these observations are indicated by data suggesting that SHP2 activation and ICSBP deficiency might coexist in human myeloid malignancies.
TITLE: Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia
AUTHOR CONTACT:
Elizabeth A. Eklund
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Phone: (312) 503-4625; Fax: (312) 908-5717; E-mail: e-eklund@northwestern.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33742
Journal
Journal of Clinical Investigation