β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage

Abstract

Activation of TGF-β by dendritic cells (DCs) expressing αvβ8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal antigens. We have recently shown that αvβ8 integrin is preferentially expressed by CD103+ DCs, and confers their ability to activate TGF-β and generate Tregs. However, how these DCs become specialized for this vital function is unknown. Here we show that β8 expression is controlled by a combination of factors that include DC lineage, and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-β itself, along with retinoic acid (RA) and Toll-like receptor (TLR) signaling, drive expression of αvβ8 in DCs. However, these signals only result in high levels of β8 expression in cells of the cDC1 lineage, CD8α+ or CD103+CD11b− DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory αvβ8-expressing DCs specialized for activation of TGF-β to facilitate Treg generation.

Transforming growth factor β: a master regulator of the gut microbiota and immune cell interactions

“…Microbiota‐derived products were also reported to influence the TGF‐β production by lamina propria DCs, including ATP (adenosine 5′‐triphosphate), which increases the expression of TGF‐β in a CD70 high subset of DCs of the small intestine. Similarly to the effects of short‐chain fatty acids on IECs, microbiota‐derived ATP can both directly increase IEC TGF‐β production and indirectly increase active TGF‐β levels by promoting integrin αvβ8 expression at the surface of DCs 42 . After dextran sodium sulfate treatment, Clostridium butyricum was recently reported to enhance TGF‐β production by colonic lamina propria DCs mainly in a TLR2, AP1–ERK pathway‐dependent manner 23 .…”

“…After dextran sodium sulfate treatment, Clostridium butyricum was recently reported to enhance TGF‐β production by colonic lamina propria DCs mainly in a TLR2, AP1–ERK pathway‐dependent manner 23 . Furthermore, microbiota‐mediated TLR signaling in intestinal DCs also promotes the expression of the integrin αvβ8 essential for TGF‐β activation 42 . The long co‐evolution of commensal bacteria and the mammalian gut has resulted in multiple mechanisms to increase TGF‐β levels, which include microbiota‐induced TGF‐β production as well as enhancement of active and hence functional TGF‐β levels.…”

Host–microbiota interactions: epigenomic regulation

“…Butyrate activation of GPR109A and CpG oligodeoxynucleotide/TLR9 stimulation were found to modulate retinoic acid signaling in DCs [36]. Activation of retinoic acid signaling in DCs was later shown to increase enrichment of active enhancer histone marks, H3K4me1 and H3K27Ac, at the avb8 integrin (Itgb8) locus in DCs, resulting in increased Itgb8 expression and enhanced Treg generation [37]. …”

The many ways tissue phagocytes respond to dying cells

“…214,215 Intestinal CD103 + DC express the αvβ8 integrin, which activates latent TGFβ and induces T REG cell generation. 214,[216][217][218] These studies strongly implicate apoptotic cellstimulated TGFβ production in the generation of T REG cells. Evidence in vivo linking T REG cells to apoptotic cell engulfment comes from several studies.…”

“…Intestinal CD103 + and not CD103 − DC could induce T REG cell differentiation without exogenously added TGF-β (213, 214). Intestinal CD103 + DC express the αvβ8 integrin, which activates latent TGF-β and induces T REG cell generation (213, 215–217). These studies strongly implicate apoptotic cell-stimulated TGF-β production in the generation of T REG cells.…”