Inflammatory cues enhance TGFβ activation by distinct subsets of human intestinal dendritic cells via integrin αvβ8

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 Tcells 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+ Tcells, 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.

Mesenteric lymph node stromal cell‐derived extracellular vesicles contribute to peripheral de novo induction of Foxp3+ regulatory T cells

“…Since TGF‐β is produced as an inactive complex, it is critical to understand how FRC‐derived TGF‐β is activated. We found an elevated expression of Itgb8 in mLN‐iFRCs as compared to pLN‐iFRCs, suggesting that similar to intestinal DCs and Tregs iFRCs can activate TGF‐β in an integrin β 8 ‐dependent manner. This observation is in line to previous findings from ex vivo mLN and pLN stromal cells .…”

“…Additionally, RNAseq analysis revealed significantly elevated expression of Itgb8 (integrin β 8 ) in mLN-iFRCs as compared to pLN-iFRCs (log2FC -2.22, adjusted p-value < 0.0001, Supporting Information Fig. 2), providing a possible mechanism of processing iFRC-derived TGF-β1 [33][34][35]. Collectively, our data suggest that TGF-β is a major mediator of the superior Treg-inducing properties of mLN-iFRCs, which furthermore display elevated expression levels of the TGF-β-activating integrin β 8 .…”

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

“…Another study reported that avb8 integrin was highly expressed in dendritic cells (DCs) in the human intestine. Indeed, avb8 integrin expression on DCs was upregulated in IBD patients and by microbial stimuli [29]. These data suggest that TGF-b production and activation by immune cells, especially DCs, are necessary for inhibiting intestinal inflammation in IBD patients.…”

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

“…Transforming growth factor‐ β (TGF‐ β ) is indispensable for generation of Treg cells in the intestine by CD103 + DCs, with activation of TGF‐ β by intestinal DCs specifically being required for Treg cell generation and prevention of colitis . Interactions between the microbiota and intestinal DCs are likely to modulate these events given the direct effects of bacterially derived lipopolysaccharide (LPS) on the induction of the TGF‐ β ‐activating integrin α v / β 8 by DCs . Integrin α v / β 8 is predominantly expressed by CD103 + CD11b − DCs in the intestine (cDC1), but probably tailors cross‐talk between DC subsets in the intestine as TGF‐ β plays a fundamental role in the development and Treg‐generating function of CD103 + CD11b + intestinal DCs (cDC2) …”

“…21 Interactions between the microbiota and intestinal DCs are likely to modulate these events given the direct effects of bacterially derived lipopolysaccharide (LPS) on the induction of the TGF-b-activating integrin a v /b 8 by DCs. 22 Integrin a v /b 8 is predominantly expressed by CD103 + CD11b À DCs in the intestine (cDC1) 23 , but probably tailors cross-talk between DC subsets in the intestine as TGF-b plays a fundamental role in the development and Treg-generating function of CD103 + CD11b + intestinal DCs (cDC2). 24 Hence, evidence indicates that the overall effects of the microbiota and its products on intestinal DCs enhance 25 corresponding with the enhanced microbial load in the colon.…”