title: The metalloprotease ADAM12 regulates the effector function of human Th17 cells.
abstract: A key modulator of immune homeostasis, TGFβ has an important role in the differentiation of regulatory T cells (Tregs) and IL-17-secreting T cells (Th17). How TGFβ regulates these functionally opposing T cell subsets is not well understood. We determined that an ADAM family metalloprotease called ADAM12 is specifically and highly expressed in both Tregs and CCR6+ Th17 cells. ADAM12 is induced in vitro upon differentiation of naïve T cells to Th17 cells or IL-17-secreting Tregs. Remarkably, silencing ADAM12 expression in CCR6+ memory T cells enhances the production of Th17 cytokines, similar to suppressing TGFβ signaling. Further, ADAM12 knockdown in naïve human T cells polarized towards Th17/Treg cells, or ectopically expressing RORC, greatly enhances IL-17-secreting cell differentiation, more potently then inhibiting TGFβ signals. Together, our findings reveal a novel regulatory role for ADAM12 in Th17 cell differentiation or function and may have implications in regulating their aberrant responses during immune pathologies.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Angela X
authors.initials: AX
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Aimee
authors.initials: A
authors.lastname: El Hed
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Frances
authors.initials: F
authors.lastname: Mercer
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America ; Department of Pathology, New York University School of Medicine, New York, New York, United States of America ; Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D054399:Receptors, CCR6 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism*
chemical_list: C106311:CCR6 protein, human; D020381:Interleukin-17; D008565:Membrane Proteins; D054399:Receptors, CCR6; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human