The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells |
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| Authors: | Angela X Zhou Aimee El Hed Frances Mercer Lina Kozhaya Derya Unutmaz |
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| Institution: | 1. Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.; 2. Department of Pathology, New York University School of Medicine, New York, New York, United States of America.; 3. Department of Medicine, New York University School of Medicine, New York, New York, United States of America.; Emory University School of Medicine, United States of America, |
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| 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. |
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