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- Title
Metalloproteases regulate T-cell proliferation and effector function via LAG-3.
- Authors
Nianyu Li; Yao Wang; Forbes, Karen; Vignali, Kate M.; Heale, Bret S.; Saftig, Paul; Hartmann, Dieter; Black, Roy A.; Rossi, John J.; Blobel, Carl P.; Dempsey, Peter J.; Workman, Creg J.; Vignali, Dario A. A.
- 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 PKCθ-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.
- Subjects
METALLOPROTEINASES; T cells; CELL proliferation; CELL physiology; IMMUNE response; CYTOKINES
- Publication
EMBO Journal, 2007, Vol 26, Issue 2, p494
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7601520