Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation

John J Worthington,Aoife Kelly,Catherine Smedley,David Bauché,Simon Campbell,Julien C Marie,Mark A Travis

doi:10.1016/j.immuni.2015.04.012

Abstract

SummaryRegulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation.

Highlights

Regulatory T (Treg) cells, a subset of CD4+ T cells expressing the transcription factor Foxp3, are crucial in regulating self-harmful T cell responses
We show that effector Treg cells express high amounts of the integrin avb8, which enables them to activate latent transforming growth factor-b (TGF-b)
We focused on the potential role of integrin avb8, which we have previously shown to be expressed by tolerogenic dendritic cells, enabling them to activate TGF-b, a pathway that is crucial in controlling immune homeostasis and responses to infection (Travis et al, 2007; Worthington et al, 2011b, 2013)

Summary

Introduction

Regulatory T (Treg) cells, a subset of CD4+ T cells expressing the transcription factor Foxp, are crucial in regulating self-harmful T cell responses. Treg cells can develop in the thymus (so-called thymic Treg cells [tTreg cells]) or be induced in the periphery via upregulation of Foxp (pTreg cells) (Rudensky, 2011). The transfer of Treg cells into mouse models of inflammatory disease actively suppresses harmful T cells to prevent inflammation (Maloy and Powrie, 2011). There are current clinical trials using Treg cells that attempt to dampen T cell responses in several human inflammatory disorders (Tang and Bluestone, 2013). It is paramount that the mechanisms by which Treg cells control immunity be determined, to identify pathways that can be targeted to promote Treg cell function

Results

Discussion

Conclusion