Dendritic Cell Subsets in Intestinal Immunity and Inflammation Tian Sun, Albert Nguyen and Jennifer L. Gommerman This information is current as J Immunol 2020; 204:1075-1083; ; of September 28, 2021. doi: 10.4049/jimmunol.1900710 http://www.jimmunol.org/content/204/5/1075 Downloaded from References This article cites 152 articles, 56 of which you can access for free at: http://www.jimmunol.org/content/204/5/1075.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Dendritic Cell Subsets in Intestinal Immunity and Inflammation Tian Sun, Albert Nguyen, and Jennifer L. Gommerman The mammalian intestine is a complex environment shaping the ensuing immune response. In this Brief Review,we that is constantly exposed to Ags derived from food, review the different types of classical DC (cDC) located in the microbiota, and metabolites. Intestinal dendritic cells LP and the GALT, as well as discuss how cDC subsets balance (DC) have the responsibility of establishing oral toler- tolerance and inflammation in both mice and humans. ance against these Ags while initiating immune re- sponses against mucosal pathogens. We now know cDC subsets that DC are a heterogeneous population of innate im- DC are composed of a largely heterogenous population of mune cells composed of classical and monocyte-derived APCs that can be mostly divided up into cDC, plasmacytoid Downloaded from DC, Langerhans cells, and plasmacytoid DC. In the DC (pDC), and monocyte-derived DC. Although it should be intestine, DC are found in organized lymphoid tissues, noted that all of the mentioned DC types can be found in the such as the mesenteric lymph nodes and Peyer’s patches, intestinal LP and GALT and they each exhibit unique func- as well as in the lamina propria. In this Brief Review,we tions, this review focuses in particular on cDC. review recent work that describes a division of labor cDC exhibit superior capacity for taking up, processing, and http://www.jimmunol.org/ between and collaboration among gut DC subsets in presenting Ags to naive T cells (4). Bona fide cDC express high the context of intestinal homeostasis and inflammation. levels of CD11c and MHC class II (MHC-II), lack the ex- Understanding relationships between DC subtypes and pression of macrophage-associated markers CD64 and F4/80, their biological functions will rationalize oral vaccine and express the transcription factor ZBTB46 (5). cDC can be further grouped into type 1 cDC (cDC1) and type 2 cDC design and will provide insights into treatments that + (cDC2): the former are superior at initiating cytotoxic CD8 quiet pathological intestinal inflammation. The Journal T cell and Th1 responses, whereas the latter excel at inducing of Immunology, 2020, 204: 1075–1083. and maintaining Th2, Th17, and T regulatory (Treg) re- sponses (6). Within gut lymphoid tissues, cDC1 can be iden- by guest on September 28, 2021 2 2 he mammalian intestine is a complex environment tified as CD4 CD8a+CD11b and cDC2 can be identified as 2 that is constantly exposed to an array of Ags derived CD4+CD8a CD11b+ (Table I). In gut nonlymphoid tis- 2 from food and the microbiota. It is estimated that we sues, cDC1 are usually classified as CD103+CD11b whereas T + + 2 + ingest over 100 g of foreign protein per day in our diet (1). cDC2 comprise both CD103 CD11b and CD103 CD11b Added to this potential antigenic load, the human intestine is (Table I). It is important to note that because macrophages are a 2 colonized by ∼1013 bacteria (2). Physical and immunological major component in the CD103 CD11b+ population, macro- barriers in the intestine prevent these Ags from triggering po- phage markers (CD64, F4/80, CX3CR1) should be included to tentially detrimental immune responses. The physical barrier is differentiate true DC versus macrophages (7). composed of mucus and glycocalyx that coat a single layer Because of the demonstration of nonredundant roles between 2 of epithelial cells (3). The immunological barrier includes the CD103+ and CD103 cDC2 subsets and their differ- intraepithelial lymphocytes and immune cells residing in ential reliance on certain transcription and metabolic factors, the intestinal lamina propria (LP) and the GALT. LP- and we have attempted to discern which particular cDC2 subset GALT-resident dendritic cells (DC) have been particularly contributes to a described phenotype wherever possible. For implicated both in the maintenance of tolerance toward example, cDC subsets can be identified based on their devel- the commensal microbiota and food and in the generation of opmental requirement for certain transcription factors includ- protective immune responses against pathogens. This impres- ing IRF8 and BATF3 (cDC1) or IRF4 (all cDC2) and RBP-J sive flexibility in function is due in part to the ability of DC to (CD103+CD11b+ cDC2). Furthermore, although the field is sense and integrate signals from their local environment, thus adapting a new marker system to classify cDC across species Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Abbreviations used in this article: cDC, classical DC; cDC1, type 1 cDC; cDC2, type 2 Ontario M5S1A8, Canada cDC; CSR, class switch recombination; DC, dendritic cell; FAE, follicle-associated epithelium; IBD, inflammatory bowel disease; ILC, innate lymphoid cell; LN, lymph ORCIDs: 0000-0002-5991-0477 (T.S.); 0000-0001-8724-7476 (A.N.). node; LP, lamina propria; LTbR, lymphotoxin b receptor; MHC-II, MHC class II; Received for publication June 24, 2019. Accepted for publication October 11, 2019. MLN, mesenteric lymph node; pDC, plasmacytoid DC; PP, Peyer’s patch; RA, retinoid acid; RALDH, retinaldehyde dehydrogenase; SILT, solitary isolated lymphoid tissue; This work was supported by a Foundation Grant (15992) from the Canadian Institutes Tfh, T follicular helper cell; Treg, T regulatory cell. of Health Research to J.L.G. Address correspondence and reprint requests to Jennifer L. Gommerman, Department of Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 Immunology, Faculty of Medicine, University of Toronto, 1 King’s College Circle 7310, Toronto, ON M5S1A8, Canada. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900710 1076 BRIEF REVIEWS: INTESTINAL DENDRITIC CELLS IN IMMUNITY Table I. cDC subsets in the mouse intestine cDC1a,b cDC2a,c 2 2 PP CD8a+CD11b CD8a CD11b+ 2 2 MLN resident CD8a+CD11b CD8a CD11b+ + 2 2 + + lo MLN migratory CD103 CD11b CX3CR1 CD103 CD11b CX3CR1 d + 2 2 + + lo Intestinal LP CD103 CD11b CX3CR1 Subset 1: CD103 CD11b CX3CR1 2 + int Subset 2: CD103 CD11b CX3CR1 2 CD103 migratory cDC2 have also been described (138) aCD11c+MHC-II+ Linneg (F4/80, CD64, CD3, B220, NK1.1). 2 2 bHistorically defined as CD8a+CD11b and more recently as XCR1+SIRPa . 2 2 cHistorically defined as CD8a CD11b+ and more recently as XCR1 SIRPa+. dFor other markers, see Refs. 9, 11, and 12. and tissues using SIRPa and XCR1 (8), for the purposes of this functionally and phenotypically heterogenous population, review we will use the CD103/CD11b “historical” markers to care must be taken in interpreting results generated using differentiate cDC subtypes because the majority of the litera- these tools. We list some commonly used mouse models in ture is based on this nomenclature. Table II. Recent reviews also provide detailed comparisons of different mouse models studying DC and DC subsets Downloaded from Tools to study DC and DC subsets (18, 19). DC functions can be studied in vitro and in vivo. To assess Anatomical distribution of cDC in the gut DC functionality in vitro, DC subsets are typically sorted based on their surface markers (Table I) and then cultured The organized structures of the GALT and the gut-draining with danger- or pathogen-associated molecular patterns, Ags, lymph nodes (LNs) are the principal locations for priming cytokines, and transgenic reporter T cells to read out priming adaptive immune cells in the intestine. The GALT is comprised http://www.jimmunol.org/ capacity. To isolate DC from the intestinal LP, an enzymatic of Peyer’s patches (PPs), caecal patches, and colonic patches. In strategy is usually needed because of the dense network of ex- addition, smaller lymphoid aggregates (isolated lymphoid fol- tracellular matrix proteins in this location. Different combi- licles and cryptopatches), collectively termed solitary isolated nations of enzymes such as collagenase and dispase can be used lymphoid tissues (SILTs), are distributed along both the small to optimize the DC yield. It should be noted, however, that and large intestine (51). As in other tissues, cDC play an enzymatic treatment may result in loss of cell-surface mole- important role in mounting appropriate immune responses cules, and the yield varies from batch to batch (13). Lymphatic against intestinal Ags. The individual features of the in- DC migrating from the intestine to the mesenteric lymph testinal LP, gut-draining LNs, and PPs are discussed be- by guest on September 28, 2021 nodes (MLNs) can be collected by mesenteric lymphadenec- low, together with the cDC populations residing in each tomy and thoracic duct cannulation (14).