JCI table of contents: August 17, 2006
PTEN: the Treg's handbrake
Naturally occurring CD4+CD25+ Tregs are a specialized subpopulation of T cells that function to prevent other T cells destroying self-tissues. But harnessing the therapeutic potential of Tregs -- for example, to treat autoimmune diseases such as diabetes and rheumatoid arthritis -- is hampered by problems generating sufficient cells to be therapeutically effective. This is because, unlike non-regulatory T cells, Tregs do not proliferate in vitro when stimulated through either their TCR or IL-2 receptor alone.
Now, in a study appearing online on August 17 in advance of print publication in the September issue of the Journal of Clinical Investigation, Laurence Turka and colleagues from the University of Pennsylvania have shown that Tregs from mice with T cells that lack phosphatase and tensin homolog (PTEN) proliferate in response to IL-2. Importantly, PTEN-deficient Tregs retained their suppressive function in vitro and in vivo, indicating that loss of PTEN by Tregs only affects their proliferative capabilities in response to IL-2 and not their other functions. These results identify PTEN as a key protein that regulates the lack of responsiveness of Tregs to IL-2 and could provide researchers with a way to overcome one of the biggest obstacles to harnessing their therapeutic potential.
TITLE: PTEN inhibits IL-2 receptor–mediated expansion of CD4+CD25+ Tregs
Laurence A. Turka
University of Pennsylvania
Philadelphia, Pennsylvania, USA
Phone: (215) 898-1018
Fax: (215) 573-2880
E-mail: [email protected].
View the PDF of this article at: https://www.the-jci.org/article.php?id=28057
Always the gentleman: CaMKII opens the door for calcium to enter
Aldosterone has recently been identified as a pathogenic stimulus of heart failure. It is produced by cells of the adrenal gland if their intracellular Ca2+ concentration is elevated, such as occurs after stimulation with angiotensin II. Although Ca2+/calmodulin-dependent kinase II (CaMKII) is known to regulate the Ca2+ channels (such as a1H T-type Ca2+ channels) that must be opened to maintain the elevated concentration of intracellular Ca2+ that is required to sustain the production of aldosterone, its mechanism of action had not been determined. Now, in a study appearing online on August 17 in advance of print publication in the September issue of the Journal of Clinical Investigation, Paula Barrett and colleagues from Virginia University School of Medicine have shown that in both activated cells in culture and rats infused with angiotensin II, CaMKII phosphorylates a serine residue of a1H T-type Ca2+ channels, which leads to an increase in the intracellular Ca2+ concentration. Blocking this phosphorylation step in rats decreased the amount of aldosterone produced in response to angiotensin II. This study provides new insight into the molecular mechanisms by which CaMKII regulates a1H T-type Ca2+ channels and might provide new therapeutic approaches to regulating aldosterone production.
TITLE: Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II
Paula Q. Barrett
University of Virginia School of Medicine
Charlottesville, Virginia, USA
Phone : (434) 924-5454
Fax: (434) 982-3878
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=27918
Fc-gamma RIII: the alternative to the TCR for NKT cell–activation
A small subpopulation of T cells known as NKT cells (because in addition to proteins expressed by other T cell–populations they also express markers of NK cells, which are a distinct immune cell–type) promotes disease in an antibody-induced mouse model of arthritis. But researchers have yet to determine how the NKT cells are activated to cause disease in this model of arthritis. In a study appearing online on August 17 in advance of print publication in the September issue of the Journal of Clinical Investigation, Doo Hyun Chung and colleagues from Seoul National University College of Medicine show that engagement of Fc-gamma receptor III (Fc-gamma RIII) by aggregated IgG can activate NKT cells and promote disease. The authors showed that the only Fc-gamma receptor expressed by NKT cells is Fc-gamma RIII and that stimulation of NKT cells through this receptor using aggregated IgG was sufficient to activate the cells. Importantly, wild-type NKT cells, but not NKT cells lacking Fc-gamma RIII, mediated antibody-induced joint inflammation when transferred to mice lacking NKT cells and the ability to stimulate NKT cells through their TCR. The demonstration in this study that NKT cells can be activated by stimulation through Fc-gamma RIII alone should impact approaches for the treatment of autoantibody-induced joint inflammation.
TITLE: Fc-gamma RIII engagement provides activating signals to NKT cells in antibody-induced joint inflammation
Doo Hyun Chung
Seoul National University College of Medicine
Seoul, Republic of Korea
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=27219
IRAK-M mediates immunosuppression during sepsis
Although sepsis is a life-threatening condition caused, in part, by an initial massive pro-inflammatory response, individuals with sepsis later become immunosuppressed, which renders them susceptible to secondary infections -- such as bacterial pneumonia. One immune cell–type that is clearly impaired in patients with sepsis is the macrophage. For example, macrophages isolated from the lungs of individuals with sepsis fail to respond normally to microbial components. Identifying the molecular events behind this defect is an area of intensive investigation.
In a study appearing online on August 17 in advance of print publication in the September issue of the Journal of Clinical Investigation, Jane Deng and colleagues from UCLA showed that in a mouse model of sepsis the macrophage immunosuppressive phenotype is associated with increased levels of IL-1 receptor–associated kinase-M (IRAK-M) -- which is a negative regulator of signaling through several cellular sensors of microbial components (TLRs). Compared with septic wild-type mice, septic IRAK-M–deficient mice were less susceptible to infection with Pseudomonas aeruginosa and cleared bacteria from the lung more rapidly, probably through the increased numbers of neutrophils that were found to be recruited to the lungs of the septic IRAK-M–deficient mice. If future studies indicate a role for IRAK-M in sepsis-induced susceptibility to secondary infection with other pathogens it could be a viable therapeutic target for the treatment of individuals with sepsis.
TITLE: Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M
Jane C. Deng
David Geffen School of Medicine at UCLA
Los Angeles, California, USA
Phone: (310) 825-0930
Fax: (310) 206-8622
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=28054
Homing in on the FoxO1 motif that regulates transcription
Insulin resistance, which is a central feature of metabolic diseases, leads to increased production of glucose in the liver. This is, in part, because of impaired negative regulation by insulin of the forkhead transcription factor FoxO1, which induces the expression of several genes that encode enzymes that promote glucose production in the liver. Despite this knowledge, researchers have yet to identify the part of FoxO1 that is necessary for its function as a promoter of glucose production.
Now, in a study appearing online on August 17 in advance of print publication in the September issue of the Journal of Clinical Investigation, Jun Nakae and colleagues from Kobe University Graduate School of Medicine have shown that the LXXLL motif (where L is leucine and X is any amino acid) is crucial for mouse FoxO1 to induce the transcription of enzymes that promote glucose production in the liver. In cultured cells, a form of FoxO1 in which the LXXLL motif was disrupted was unable to induce the expression of several genes that encode enzymes that promote glucose production in the liver and was unable to interact with Sirt1. Overexpression of the mutant form of FoxO1 in leptin receptor–deficient mice suppressed glucose production in the liver and ameliorated their insulin-resistant phenotype. The authors therefore suggest that the LXXLL motif could be targeted to modulate the function of FoxO1 for the treatment of metabolic disorders.
TITLE: The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity
Kobe University Graduate School of Medicine
E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25518
Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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