EDITOR'S PICK: Regulatory T cells require WASp if they are to prevent self-destruction
In humans, mutation of the gene encoding a protein known as WASp leads to susceptibility to infections and systemic autoimmunity. Most studies have focused on understanding the defects in T cell activation caused by the WASp deficiency, but researchers at the University of Washington in Seattle have now found that in mice and humans a population of T cells known as regulatory T cells (Treg), which keep other immune cells from attacking the body's own tissues and causing autoimmunity, are also impaired in the absence of WASp.
In the study, which appears online on January 11 in advance of publication in the February print issue of the Journal of Clinical Investigation, David Rawlings and colleagues show that like WASp-deficient humans, WASp-deficient mice develop systemic autoimmune disease. This was not due to a defect in the number of Treg that developed in the mice, but due to a defect in their ability to control autoimmunity. Consistent with this, the peripheral blood of a WASp-deficient patient in whom a spontaneous revertant mutation occurred had substantial numbers of WASp+ Treg. These cells were able to ameliorate this individual's recurrent episodes of autoimmune hemolytic anemia, indicating that a defect in Treg function is likely to contribute to the systemic autoimmunity from which individuals lacking WASp suffer.
TITLE: Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
AUTHOR CONTACT:
David J. Rawlings
University of Washington School of Medicine, Seattle, Washington, USA.
Phone: (206) 987-7450; Fax: (206) 987-7310; E-mail: drawling@u.washington.edu.
Jennifer Seymour
Media Relations Manager
Children's Hospital and Regional Medical Center, Seattle, Washington, USA.
Phone: (206) 987-5207; Fax: (206) 987-5215; E-mail: jennifer.seymour@seattlechildrens.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=29539
ONCOLOGY: Tumor cells replace the need for growth factors by using other stimulators
One feature of tumor cells that makes them cancerous is their ability to grow in the absence of the signals that normal cells require to grow. For example, breast cancer is often associated with the ability of the tumor cells to grow in the absence of a growth factor known as EGF. In many cases, the tumor cells become independent of EGF through genetic mutations that result in the receptor for EGF or its downstream signaling proteins becoming constantly activated. However, a study using a human breast cancer cell line, which appears online on January 11 in advance of publication in the February print issue of the Journal of Clinical Investigation, shows that increased amounts of another molecule that can activate the EGF receptor (TGF-alpha) can also cause the tumor cells to become independent of EGF.
Mina Bissell and Paraic Kenny from the University of California, Berkeley, showed that a human breast cancer cell line expressed high levels of TGF-alpha, which can bind and activate the EGF receptor. Expression of high levels of TGF-alpha required a protein known as TACE, which cleaves a precursor form of TGF-alpha to generate the active form of the protein, and inhibition of TACE impaired the tumorigenic potential of the breast cancer cell line. Importantly, high levels of expression of TGF-alpha and TACE were found to correlate with and be predictive of a poor outcome in patients with breast cancer. This study therefore identifies a new pathway by which tumor cells can become independent of EGF, and the authors suggest that targeting this pathway might provide a new approach to treating breast cancer and other cancers in which the tumor cells grow independently of EGF, such as colon cancer.
TITLE: Targeting TACE-dependent EGFR ligand shedding in breast cancer
AUTHOR CONTACT:
Mina J. Bissell
University of California, Berkeley, California, USA.
Phone: (510) 486-4365; Fax: 510) 486-5586; E-mail: mjbissell@lbl.gov.
Paraic A. Kenny
University of California, Berkeley, California, USA.
Phone: (510) 486-4365; Fax: 510) 486-5586; E-mail: pakenny@lbl.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29518
Journal
Journal of Clinical Investigation