title: Metalloproteases regulate T-cell proliferation and effector function via LAG-3.
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 approximately 12-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.
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Nianyu
authors.initials: N
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Forbes
authors.forename: Kate M
authors.initials: KM
authors.lastname: Vignali
authors.forename: Bret S
authors.initials: BS
authors.lastname: Heale
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Dieter
authors.initials: D
authors.lastname: Hartmann
authors.forename: Roy A
authors.initials: RA
authors.lastname: Black
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dempsey
authors.forename: Creg J
authors.initials: CJ
authors.lastname: Workman
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D008565:Membrane Proteins / Q000502:physiology; D045726:Metalloproteases / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D000093322:Lymphocyte Activation Gene 3 Protein