Inflammatory cues enhance TGF\u03b2 activation by distinct subsets of human intestinal dendritic cells via integrin \u03b1v\u03b28

T.M Fenton,S Campbell,J.J Worthington,D Sheppard,C Smedley,S.L Nishimura,F Powrie,A Atakilit,S Levison,E.E Shuttleworth,A Kelly,M.A Travis,M.J Lehtinen

doi:10.1038/mi.2016.94

Abstract

Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-β (TGFβ), which is secreted by cells as a latent complex that requires activation to function. However, how TGFβ activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFβ, integrin αvβ8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c+ but not the CD141+ intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGFβ-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin αvβ8 expression and TGFβ activation by human DC. We also show that DC expression of integrin αvβ8 enhanced induction of FOXP3 in CD4+ T cells, suggesting functional importance of integrin αvβ8 expression by human DC. These results show that microbial signals enhance the TGFβ-activating ability of human DC via regulation of integrin αvβ8 expression, and that intestinal inflammation may drive this pathway in patients with IBD.

Highlights

The intestine is a challenging environment for the immune system, which must induce protective responses against foodborne pathogens, but promote tolerance against the trillions of microorganisms that compose the microbiota
We examined expression of integrin avb[8] by flow cytometry on human intestinal dendritic cells (DCs), using an antibody we generated that binds to human integrin b8
We find that the transforming growth factor-b (TGFb)-activating integrin, avb[8], is expressed on human intestinal CD1c þ DC, and that expression is increased on this DC subset in patients with Crohn’s disease (CD)

Summary

Introduction

The intestine is a challenging environment for the immune system, which must induce protective responses against foodborne pathogens, but promote tolerance against the trillions of microorganisms that compose the microbiota. It is proposed that specialized regulatory mechanisms are in place to balance protective and tolerogenic immunity in the gut, with failure of these mechanisms resulting in inflammatory bowel disease (IBD).[1]. T-cell responses, promoting differentiation of both Foxp[3] þ regulatory T cells (Tregs) and T helper type 17 cells, and suppressing the differentiation of T helper type 1 and T helper type 2 cells.[2] recent evidence suggests that targeting the TGFb pathway in IBD may have beneficial effects in some patients.[3] Many different cells in the gut produce TGFb, but always as a latent complex, which has to be activated to function. Regulation of TGFb function is critically controlled at the level of its activation

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