PD-L1+ and XCR1+ dendritic cells are region-specific regulators of gut homeostasis

Rafael M Rezende,David C A Lima,Howard L Weiner,Mariana A Oliveira,Galina Gabriely,Jeffrey Leibowitz,Anya Song,Lydia Guo,Ana C Anderson,Oleg Butovsky,Eduardo L C Lobo,Brenda N Nakagaki,Thais G Moreira,Christian D Gauthier,Valerie Willocq,Ana Maria C Faria,Laura M Cox,Davide Mangani,Gopal Murugaiyan

doi:10.1038/s41467-021-25115-3

Abstract

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.

Highlights

The intestinal mucosa constitutes an environment of closely regulated immune cells
We found that XCR1− Dendritic cells (DC) had higher expression of Irf[4], which is associated with Sirpα+ cDC2s and decreased levels of Irf[8] (Fig. 4d, e), which is associated with XCR1+ cDC1s36
Esterhazy et al.[17] have shown that gut-draining lymph nodes are specific to the functional gut segment to which they are associated and that the DC signature and polarization of T cells differ between segment-specific draining lymph nodes

Summary

Introduction

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. DCs have been characterized in gut lymph nodes the features of intestinal LP are unknown This is important as intestinal DCs have a key physiologic function in maintaining gut homeostasis. It is not clear whether DCs residing in distinct intestinal compartments are functionally unique and drive different T-cell responses. Using RNA sequencing and mass and flow cytometry, we characterize DCs throughout the intestine and show that the small intestine is enriched in PD-L1+ DCs, whereas the large intestine is enriched in XCR1+ DCs. Mice lacking programmed death 1 (PD-1)-L1+ or XCR1+ DCs exhibit a pro-inflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells in the models of 5-FU-induced mucositis and dextran sodium sulfate (DSS)-induced colitis. Our findings identify regional-specific compartmentalization of distinct intestinal DC signatures at the level of adaptive immunity and outline a framework for understanding the refinement and robustness of gut homeostasis

Methods

Results

Conclusion