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  • The EMBO Journal (2007) 26, 494 - 504
  • doi:10.1038/sj.emboj.7601520

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

  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

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

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 approx12-fold following T-cell activation, whereas LAG-3 shedding by ADAM17 is induced by TCR signaling in a PKCtheta-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