The Metalloprotease ADAM12 Regulates the Effector Function of Human Th17 Cells

Angela X Zhou,Aimee El Hed,Frances Mercer,Lina Kozhaya,Derya Unutmaz

doi:10.1371/journal.pone.0081146

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.

Highlights

Th17 cells are characterized by their secretion of IL-17, an inflammation-inducing cytokine that is implicated in the pathogenesis of several autoimmune processes, including asthma, systemic lupus erythematosus, colitis and allograft rejection [1]
We found that ADAM12 expression was much higher in IL-17-secreting T cells, and correlated with RORC and IL-17 mRNA expression (Figure 1C)
We discovered that silencing ADAM12 expression greatly enhanced the production of Th17 cytokines

Summary

Introduction

Th17 cells are characterized by their secretion of IL-17, an inflammation-inducing cytokine that is implicated in the pathogenesis of several autoimmune processes, including asthma, systemic lupus erythematosus, colitis and allograft rejection [1]. Th17 cell differentiation requires the combination of TGFβ and pro-inflammatory cytokines including IL-6, IL-1β and IL-23 [2]. TGFβ is crucial for generating induced regulatory T cells, a portion of which secrete IL-17, and have anti-inflammatory functions in controlling excessive immune response [3,4,5,6]. How TGFβ signals regulate programming of these functionally distinct IL-17-secreting T cell subsets are not well understood. A recent study suggested that a member of the ADAM (a disintegrin and metalloprotease) family of metalloproteases, ADAM12, could interact with TGFβRII [11] and that this interaction could enhance TGFβ signaling through control of TGFβR localization and stability on early endosomes [11,12]

Methods

Results

Conclusion