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Metalloproteases regulate T-cell proliferation and effector function via LAG-3
- Publication Year :
- 2007
- Publisher :
- Nature Publishing Group, 2007.
-
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.
- Subjects :
- medicine.medical_treatment
T cell
T-Lymphocytes
Receptors, Antigen, T-Cell
Mice, Transgenic
CHO Cells
Biology
ADAM17 Protein
Cleavage (embryo)
General Biochemistry, Genetics and Molecular Biology
Article
ADAM10 Protein
Mice
Cricetulus
Antigens, CD
Cricetinae
medicine
Animals
Molecular Biology
Cell Proliferation
General Immunology and Microbiology
Effector
Cell growth
General Neuroscience
T-cell receptor
Membrane Proteins
Molecular biology
Lymphocyte Activation Gene 3 Protein
Transmembrane protein
Cell biology
ADAM Proteins
Cytokine
medicine.anatomical_structure
Metalloproteases
Amyloid Precursor Protein Secretases
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....647d1ee179100f1f3c68aa8f0e737c87