Article
- The EMBO Journal (2007) 26, 494 - 504
- doi:10.1038/sj.emboj.7601520
Subject Categories:
Metalloproteases regulate T-cell proliferation and effector function via LAG-3
Nianyu Li1,a, Yao Wang1, Karen Forbes1, Kate M Vignali1, Bret S Heale2,b, Paul Saftig3, Dieter Hartmann4, Roy A Black5, John J Rossi2, Carl P Blobel6, Peter J Dempsey7,8,c, Creg J Workman1 and Dario A A Vignali1
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
- Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
- The Biochemical Institute, Christian-Albrechts University, Kiel, Germany
- Department for Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB4), Leuven, Belgium
- Department of Inflammation, Amgen Inc., Seattle, WA, USA
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, NY, USA
- Pacific Northwest Research Institute, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
Correspondence to:
Dario A A Vignali, Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. Tel.: +1 901 495 2332; Fax: +1 901 495 3107; E-mail: dario.vignali@stjude.org
aPresent Address: Department of Investigative Toxicology, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USA
bPresent Address: MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland
cPresent Address: Departments of Pediatrics and Molecular and Integrative Physiology, University of Michigan, 1150 W. Medical Ctr Drive, Ann Arbor, MI 48109-0656, USA
Received 10 October 2006; Accepted 30 November 2006
Abstract
Tight control of T-cell proliferation and effector function is essential to ensure an effective but appropriate immune response. Here, we reveal that this is controlled by the metalloprotease-mediated cleavage of LAG-3, a negative regulatory protein expressed by all activated T cells. We show that LAG-3 cleavage is mediated by two transmembrane metalloproteases, ADAM10 and ADAM17, with the activity of both modulated by two distinct T-cell receptor (TCR) signaling-dependent mechanisms. ADAM10 mediates constitutive LAG-3 cleavage but increases 
12-fold following T-cell activation, whereas LAG-3 shedding by ADAM17 is induced by TCR signaling in a PKC
-dependent manner. LAG-3 must be cleaved from the cell surface to allow for normal T-cell activation as noncleavable LAG-3 mutants prevented proliferation and cytokine production. Lastly, ADAM10 knockdown reduced wild-type but not LAG-3-/- T-cell proliferation. These data demonstrate that LAG-3 must be cleaved to allow efficient T-cell proliferation and cytokine production and establish a novel paradigm in which T-cell expansion and function are regulated by metalloprotease cleavage with LAG-3 as its sole molecular target.
Keywords:
- ADAM,
- LAG-3,
- metalloproteases,
- shedding,
- T-cell function
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning
Nature Reviews Neuroscience Perspective (01 Oct 2002)
Protein palmitoylation: a regulator of neuronal development and function
Nature Reviews Neuroscience Review (01 Oct 2002)
ADAMs: key components in EGFR signalling and development
Nature Reviews Molecular Cell Biology Review (01 Jan 2005)
RESEARCH
ADAM10 cleavage of N-cadherin and regulation of cell?cell adhesion and β-catenin nuclear signalling
The EMBO Journal Article (23 Feb 2005)
The inhibitory cytokine IL-35 contributes to regulatory T-cell function
Nature Letters to Editor (22 Nov 2007)
