Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity

Fenton, Thomas M.; Jørgensen, Poul Henrik; Niss, Kristoffer; Rubin, Samuel J.; Mörbe, Urs; Riis, Lene; Silva, Clément Da; Plumb, Adam W.; Vandamme, Julien; Jakobsen, Henrik; Brunak, Søren; Habtezion, Aida; Nielsen, Ole Haagen; Johansson‐Lindbom, Bengt; Agace, William W.

doi:10.1016/j.immuni.2020.02.001

Cited by 94 publications

(140 citation statements)

References 62 publications

(98 reference statements)

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“…It is important to note, however, that, based on data from the blood, the functionality of these cells is likely to be impaired (24,54). Further studies with larger numbers of healthy participants (e.g., subjects consenting to research biopsies) will be needed to explore in more depth the impact of HIV infection on unconventional T-cells in the different tissue compartments and to investigate potential distinctions between the lamina propria and intraepithelial intestinal tissue compartments (55).…”

Section: Discussionmentioning

confidence: 99%

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection

et al. 2020

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The intestinal mucosa is enriched for unconventional T-cells, including mucosal associated invariant T-cells (MAIT), invariant natural killer T-cells (iNKT) and γδ T-cells. These cells are activated by bacterial metabolites, lipid antigens and cytokines, and are important for intestinal barrier integrity. The loss of gut homeostasis observed in HIV infection is central to disease pathogenesis, and studies have highlighted impairment of particular unconventional T-cell subsets within a specific gut compartment. However, although the small and large intestine are distinct niches, the overall impact of HIV on unconventional T-cells across the gut mucosal has not been well-studied. We hypothesized that compartment specific differences in the unconventional T-cell repertoire would exist between the small and large intestine, due to increasing bacterial loads and microbial diversity; and that the impact of HIV infection might differ depending on the compartment examined. We used mass cytometry, flow cytometry and unbiased T-cell receptor profiling to quantify unconventional T-cells in blood and tissue from the small (duodenum) and large (colon) intestine in HIV infected and uninfected participants undergoing examination for a range of intestinal conditions. Overall, we find distinct compartmentalisation of T-cells between blood, duodenum and colon, with iNKT cells significantly enriched in the duodenum and δ-1 expressing γδ T-cells in the colon. In addition, we observe greater clonal expansion of conventional TCRs in the duodenum, suggestive of stronger adaptive immunity in this compartment. Conversely, we find evidence of an expanded unconventional TCR repertoire in the colon, which contained far more overlapping "donor unrestricted" sequences than the duodenum. Twelve of these TCRs were highly "MAIT-like" and 3 were unique to the colon, suggesting an enrichment of donor unrestricted T-cells (DURTs) in this compartment. Unexpectedly, however, no Magnoumba et al. Unconventional T-Cells and HIV Infection significant impact of HIV infection on any of the unconventional T-cell subsets measured was observed in either mucosal site in terms of frequency or TCR repertoire. Further studies are required to investigate the importance of these unconventional T-cell subsets to intestinal homeostasis within the different gut compartments and determine if they are functionally impaired during HIV infection.

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Section: Discussionmentioning

confidence: 99%

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection

et al. 2020

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“…The majority of bacteria interact indirectly with intestinal epithelial cells, mediated by food-fermented postbiotics [ 114 , 115 ]. The mucosa also serves as a source of nutrients for commensal bacteria, such as Akkermansia muciniphila , while changes in the microbiome community, mainly the ratio of Bacteroides to Firmicutes , could alter mucin glycosylation [ 116 , 117 , 118 ]. In a heathy status, gut microbiota is restricted to the outer layer of mucosa, stimulating active B cells to secrete secretory IgA (sIgA), while promoting goblet cells to produce MUC2 [ 119 ].…”

Section: Intestinal Microbiota and Ibdmentioning

confidence: 99%

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Yao

Fan

et al. 2021

Foods

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Inflammatory bowel disease (IBD), a chronic, recurring inflammatory response, is a growing global public health issue. It results from the aberrant crosstalk among environmental factors, gut microbiota, the immune system, and host genetics, with microbiota serving as the core of communication for differently-sourced signals. In the susceptible host, dysbiosis, characterized by the bloom of facultative anaerobic bacteria and the decline of community diversity and balance, can trigger an aberrant immune response that leads to reduced tolerance against commensal microbiota. In IBD, such dysbiosis has been profoundly proven in animal models, as well as clinic data analysis; however, it has not yet been conclusively ascertained whether dysbiosis actually promotes the disease or is simply a consequence of the inflammatory disorder. Better insight into the complex network of interactions between food, the intestinal microbiome, and host immune response will, therefore, contribute significantly to the diagnosis, treatment, and management of IBD. In this article, we review the ways in which the mutualistic circle of dietary nutrients, gut microbiota, and the immune system becomes anomalous during the IBD process, and discuss the roles of bacterial factors in shaping the intestinal inflammatory barrier and adjusting immune capacity.

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“…Compared with the cecum, IgA + plasma cells of the sigmoid colon respond to a rich and unevenly represented community of bacterial species; most likely accounting for the increased activation, migratory and greater clonality status of plasma cells ( 143 ). Indeed, by means of a novel method for identifying and isolating lymphoid follicles along the length of the human intestine and IgA sequencing analysis, Agace’s group showed that IgA adaptive immune responses are initiated in an anatomically restricted manner in the human Peyer’s patches and submucosal isolated lymphoid follicules contributing to the ileal and colonic plasma cell repertoires, respectively ( 152 ).…”

Section: The Gut Microbiome and The Intestinal Immune Systemmentioning

confidence: 99%

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

et al. 2020

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While colorectal cancers (CRC) are paradigmatic tumors invaded by effector memory lymphocytes, the mechanisms accounting for the relative resistance of MSI negative CRC to immunogenic cell death mediated by oxaliplatin and immune checkpoint inhibitors has remained an open conundrum. Here, we propose the viewpoint where its microenvironmental contexture could be explained -at least in part- by macroenvironmental cues constituted by the complex interplay between the epithelial barrier, its microbial ecosystem, and the local immune system. Taken together this dynamic ménage-à-trois offers novel coordinated actors of the humoral and cellular immune responses actionable to restore sensitivity to immune checkpoint inhibition. Solving this paradox involves breaking tolerance to crypt stem cells by inducing the immunogenic apoptosis of ileal cells in the context of an ileal microbiome shifted towards immunogenic bacteria using cytotoxicants. This manoeuver results in the elicitation of a productive Tfh and B cell dialogue in mesenteric lymph nodes culminating in tumor-specific memory CD8+ T cell responses sparing the normal epithelium.

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Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity

Cited by 94 publications

References 62 publications

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection

Unbiased Profiling Reveals Compartmentalization of Unconventional T-Cells Within the Intestinal Mucosa Irrespective of HIV Infection

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

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