Abstract
B7-H1 (PD-L1) on immune cells plays an important role in Tcell coinhibition by binding its receptor PD-1. Here, we show that both human and mouse intestinal epithelium express B7-H1 and that B7-H1-deficient mice are highly susceptible to dextran sodium sulfate (DSS)- or trinitrobenzenesulfonic acid (TNBS)-induced gut injury. B7-H1 deficiency during intestinal inflammation leads to high mortalityand morbidity, which are associated with severe pathological manifestations in the colon, including loss of epithelial integrity and overgrowth of commensal bacteria. Results from bone marrow chimeric and knockout mice show that B7-H1 expressed on intestinal parenchyma, but not on hematopoietic cells, controls intestinal inflammation in an adaptive immunity-independent fashion. Finally, we demonstrate that B7-H1 dampened intestinal inflammation by inhibiting tumor necrosis factor α (TNF-α) production and by stimulating interleukin 22 secretion from CD11c(+)CD11b(+) lamina propria cells. Thus, our data uncover a mechanism through which intestinal tissue-expressed B7-H1 functions as an essential ligand for innate immune cells to prevent gut inflammation.
Highlights
The gut lumen hosts 90% of the microorganisms in the human body
Since B7-H1 is mainly expressed on immune cells and PD-1 is expressed on activated T cells, research on this pathway has primarily focused on T cell coinhibition; the role of the B7-H1/PD-1 pathway in T cell-mediated intestinal inflammation and inflammatory bowel disease (IBD) remains largely unknown
To investigate B7-H1 function in gut immunity we chose a chemical model of intestinal injury utilizing oral administration of dextran sodium sulfate (DSS) that injures the colonic epithelium (Okayasu et al, 1990) and triggers potent inflammatory responses (RakoffNahoum et al, 2004)
Summary
The gut lumen hosts 90% of the microorganisms in the human body This microbiota community benefits the host by extracting energy and nutrients from food, by preventing colonization of pathogenic species (Hooper and Gordon, 2001), and by regulating immune cell function (Maloy and Powrie, 2011). Deregulation of intestinal homeostasis, with concomitant aberrant activation of mucosal innate and adaptive immunity, can result in gut injury, inflammation, and inflammatory bowel disease (IBD). The interaction between the B7 family members and their receptors provides critical costimulation and coinhibition, which regulate T cell function. Since B7-H1 is mainly expressed on immune cells and PD-1 is expressed on activated T cells, research on this pathway has primarily focused on T cell coinhibition; the role of the B7-H1/PD-1 pathway in T cell-mediated intestinal inflammation and IBD remains largely unknown. We identified epithelium-expressed B7-H1 as a key regulator of intestinal inflammation and colitis by inhibiting innate immune cells
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