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The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells

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 AD...

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Autores principales: Zhou, Angela X., El Hed, Aimee, Mercer, Frances, Kozhaya, Lina, Unutmaz, Derya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867213/
https://www.ncbi.nlm.nih.gov/pubmed/24363794
http://dx.doi.org/10.1371/journal.pone.0081146
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author Zhou, Angela X.
El Hed, Aimee
Mercer, Frances
Kozhaya, Lina
Unutmaz, Derya
author_facet Zhou, Angela X.
El Hed, Aimee
Mercer, Frances
Kozhaya, Lina
Unutmaz, Derya
author_sort Zhou, Angela X.
collection PubMed
description 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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spelling pubmed-38672132013-12-22 The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells Zhou, Angela X. El Hed, Aimee Mercer, Frances Kozhaya, Lina Unutmaz, Derya PLoS One Research Article 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. Public Library of Science 2013-11-21 /pmc/articles/PMC3867213/ /pubmed/24363794 http://dx.doi.org/10.1371/journal.pone.0081146 Text en © 2013 Zhou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhou, Angela X.
El Hed, Aimee
Mercer, Frances
Kozhaya, Lina
Unutmaz, Derya
The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells
title The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells
title_full The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells
title_fullStr The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells
title_full_unstemmed The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells
title_short The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells
title_sort metalloprotease adam12 regulates the effector function of human th17 cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867213/
https://www.ncbi.nlm.nih.gov/pubmed/24363794
http://dx.doi.org/10.1371/journal.pone.0081146
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