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| Subject Categories: Proteins | Immunology |
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| The EMBO Journal
(2007) 26, 494–504, doi:10.1038/sj.emboj.7601520 |
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| Metalloproteases regulate T-cell proliferation and effector function via LAG-3 |
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| Nianyu Li1, 9, Yao Wang1, Karen Forbes1, Kate M Vignali1, Bret S Heale2, 10, Paul Saftig3, Dieter Hartmann4, Roy A Black5, John J Rossi2, Carl P Blobel6, Peter J Dempsey7, 8, 11, Creg J Workman1 and Dario A A Vignali1 |
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1 Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA 2 Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA 3 The Biochemical Institute, Christian-Albrechts University, Kiel, Germany 4 Department for Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB4), Leuven, Belgium 5 Department of Inflammation, Amgen Inc., Seattle, WA, USA 6 Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, NY, USA 7 Pacific Northwest Research Institute, Seattle, WA, USA 8 Department of Medicine, University of Washington, Seattle, WA, USA To whom correspondence should be addressed 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 9 Present Address: Department of Investigative Toxicology, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USA 10 Present Address: MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland 11 Present 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. |
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| Abstract |
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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. |
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| Keywords: ADAM, LAG-3, metalloproteases, shedding, T-cell function |
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