ICMI 2009: all immunity is mucosal

Following his first and only electoral defeat, for a seat on the city council of Cambridge, MA, then-future Speaker of the House Tip O’Neill famously remarked, “All politics is local.” Reflecting on the highly successful 14th International Congress of Mucosal Immunology (ICMI), held 5–9 July in Boston—just across the Charles River from O’Neill’s home district—one could posit that this message applies just as well to the immune system: all immunity is local (i.e., mucosal). The theme of ICMI 2009, “reconciling immunity, tolerance and inflammation at the mucosal interface,” highlights the concept that properly regulated mucosal immunity is critical to overall health and well-being. The cells that populate the mucosal surfaces of the body are confronted on a daily basis with local challenges from microbes, food antigens, and environmental pollutants, and must inform the systemic immune system about issues that affect the body as a whole. Immune homeostasis at the mucosal level allows the body to obtain nourishment from foreign substances and to develop a mutualistic relationship with its resident microbiota, without disrupting the balance of power. By contrast, mucosal unrest can lead to local damage in the form of an unregulated inflammatory response, with the potential to spread throughout the body in the form of autoimmune and allergic diseases and even cancer. The breadth of current research in mucosal immunology was evidenced by the diversity of topics of the morning plenary sessions at ICMI 2009, including microbe–host interactions, innate immunity, epithelial cells, B- and T-cell function and regulation, novel cytokines, mucosal diseases, and mucosal vaccines. These topics were expanded on at oral and poster sessions in the afternoons and discussed well into the evenings by immunologists from all corners of the globe who appreciate that all immunity is mucosal.

One theme that bridged the many topics addressed at ICMI 2009 is the dynamic interplay between the commensal microbiota and the mucosal immune system. While the crucial role of resident bacteria in the development, activation, and regulation of immunity has long been appreciated, far less is known about the roles of specific bacterial species and interactions among species.1 Recent advances in metagenomics have greatly increased our knowledge of the composition of microbial communities at the mucosal surface2 and have triggered new interest in unraveling the complexity of host immune interactions with commensal bacteria. Nowhere is the impact of the microbiota more evident than in the intestine, where upward of 15,000 individual bacterial species inhabit the mucosal surface. It is now clear that the microbial “signature” varies widely among individuals, and that alterations in the composition of the gut microbiota (“dysbiosis”) are associated with local inflammation that can cause significant collateral damage and give rise to systemic disease. Apropos of the theme of microbe–host interactions, ICMI 2009 was kicked off by a pre-congress workshop, “Microbes and Mucosal Immunity,” which Peter Ernst (University of Virginia) and I cochaired. At the conclusion of this workshop, ICMI 2009 opened with a keynote lecture by Brett Finlay (University of British Columbia), “Studying the Microbiome in Mucosal Tissues.”

Among the many topics related to microbe–host interactions at ICMI 2009, three specific examples illustrate the contribution of microbes to immunopathology: inflammatory bowel disease (IBD), colorectal cancer, and type 1 diabetes.

In his presentation of the Tsuchiya Memorial Lecture, Charles Elson (University of Alabama at Birmingham) discussed his recent work on the interactions among the intestinal microbiota, regulatory T cells (Tregs), and immunoglobulin A (IgA) in the maintenance of intestinal homeostasis. Elson’s research has implicated the flagellar antigen CBir1 in the etiology of Crohn’s disease, a form of IBD.3,4 He presented evidence that Tregs in the gut promote the production of secretory IgA specific for antigens such as CBir1, which in turn limits systemic T-cell exposure to potentially immunogenic microbial antigens. Specific depletion of Tregs was found to cause a decrease in intestinal anti-CBir1 IgA, accompanied by increased proliferation of pro-inflammatory CBir1 effector T cells. Elson concluded that the Treg–IgA–microbiota homeostatic pathway stabilizes the gut microbiota, prevents pro-inflammatory T-cell responses, and provides resistance to colonization by pathogenic microorganisms. Another example of regulation by the microbiota of intestinal inflammation was presented by Dan Littman (New York University) in the plenary session “Novel Cytokines at Mucosal Surfaces” (chaired by Jo Viney, Amgen). Littman’s research has implicated specific species of segmented filamentous bacteria (SFB) in promoting the differentiation of pro-inflammatory helper T cells that produce interleukin (IL)-17 (Th17 cells).5 He presented evidence that mice lacking SFB in their gut microbiota have high numbers of mucosal Tregs and virtually no Th17 cells. Co-housing these mice with mice colonized with SFB was sufficient to induce development of Th17 cells and to exacerbate experimental colitis. New data from Littman’s group suggest that the balance of Tregs and Th17 cells in the gut is regulated by local concentrations of transforming growth factor-β, which at low levels promotes synthesis of the transcription factor RORγt and differentiation of Th17 cells, and at high levels promotes synthesis of the transcription factor FoxP3 and differentiation of Tregs. Other examples of bacteria that promote inflammation were presented in oral and poster sessions throughout the meeting, and it is clear that characterization of microbe–host interactions will be crucial to understanding and preventing IBD and other inflammatory diseases.

While certain types of bacteria promote intestinal inflammation, others appear to ameliorate inflammation and promote homeostasis in surprising ways. In the plenary session “Molecular Basis of Microbial–Immune Interactions at the Wet Surfaces of the Body” (chaired by Roy Curtiss, Arizona State University), Dennis Kasper (Brigham and Women’s Hospital) discussed a novel mechanism by which bacterial capsular polysaccharides can ameliorate inflammation. Kasper’s group recently reported that polysaccharide A (PSA) from Bacteroides fragilis protects mice from experimental colitis induced by Helicobacter hepaticus, a widespread commensal bacterium that can act as an opportunistic pathogen in immunocompromised hosts.6 Kasper presented evidence that PSA, either as part of intact B. fragilis or as a purified polysaccharide, ameliorates colitis through a mechanism requiring IL-10-producing helper T cells. Another example of an anti-inflammatory bacterial product was described by Brent Polk (Vanderbilt University) in the plenary session “Mucosal Epithelium.” Polk’s group has reported that soluble products from the probiotic bacterium Lactobacillus rhamnosus GG (LGG) regulate intestinal epithelial cell survival and growth, thereby enhancing barrier function and limiting exposure of bacterial antigens to the systemic immune system.7 Polk presented new data suggesting that the beneficial effects of a soluble 40-kDa protein from LGG involve stimulation of the kinase activity of the epidermal growth factor receptor in intestinal epithelial cells. Exciting new research on the anti-inflammatory effects of probiotic bacteria and their products was presented in many sessions at ICMI 2009, offering the hope that new probiotic-based therapies for inflammatory diseases will emerge in the near future.

Uncontrolled intestinal inflammation is a risk factor for epithelial neoplasia in mice with experimental colitis as well as in humans with IBD, and recent evidence has suggested that the gut microbiota may contribute to cancer development.8 In the Distinguished Keynote Lecture, “Transmissible Ulcerative Colitis and Colorectal Cancer Driven by T-bet in Dendritic Cells,” Laurie Glimcher (Harvard School of Public Health) presented convincing evidence that alterations in the colonic microbiota can contribute directly to intestinal inflammation and subsequent development of colorectal cancer. Recent work from Glimcher’s group revealed an unexpected function for the transcription factor T-bet in regulating intestinal inflammation and the composition of the colonic microbiota.9 Immunodeficient (Rag−/−) mice with a concurrent deletion in the T-bet gene spontaneously developed intestinal inflammation similar to that seen in humans with ulcerative colitis (UC), a form of IBD, and were hence termed TRUC mice. Genetically normal mice housed with TRUC mice developed colitis, suggesting that colitis is “communicable” via the gut microbiota. Glimcher presented new evidence that TRUC mice spontaneously develop epithelial neoplasia, recapitulating key features of UC-associated colorectal cancer. The TRUC epithelium was found to be hyperproliferative, with elevated expression of antiapoptotic proteins. A key role for dendritic cells (DCs) was evidenced by the findings that deletion of DCs ablated colitis and that re-expression of T-bet specifically in DCs blunted both colitis and neoplasia. Although the specific bacterial species that contribute to communicable TRUC colitis and neoplasia have not yet been identified, this exciting avenue of research offers the promise to increase our understanding of the etiology of IBD and colitis-associated cancer as well as the potential development of therapies that target the colonic microbiota.

A third example of a novel connection between the gut microbiota and inflammatory disease was presented by Alex Chervonsky (University of Chicago) in the plenary session “Molecular Basis of Microbial–Immune Interactions.” Chervonsky’s research has recently revealed an important contribution of innate immunity and the intestinal microbiota to the development of type 1 diabetes, which is characterized by autoimmune destruction of pancreatic islets.10 Interestingly, deletion of the gene encoding the Toll-like receptor adaptor protein MyD88 was found to prevent the development of islet inflammation in non-obese diabetic (NOD) mice. Dependence of this effect on the gut microbiota was evidenced by the finding that germ-free MyD88−/− mice developed robust diabetes, which could be reversed by colonization of the mice with a defined microbial consortium of bacteria typically present in the human colon. Chervonsky presented data from metagenomic analyses demonstrating that MyD88 deficiency in and of itself leads to an alteration in the composition of the gut microbiota, which in turn can contribute to systemic inflammation. This example highlights the complex interplay between microbial and host cells, and offers an explanation for the synergy between genetic and environmental factors in the development of type 1 diabetes. Future identification of specific inflammatory and protective bacterial species could lead to the development of new preventive or therapeutic strategies for type 1 diabetes and other autoimmune diseases.

These three examples offer a taste of new developments in the emerging field of microbe–host interactions in mucosal immunity, but they represent only a portion of the exciting new research in this area that was presented at ICMI 2009. Hopefully, new insights and collaborations resulting from this meeting of like-minded scientists in Boston will provide a stimulus for this promising line of research. We should be vigilant, however, to avoid falling into a “host-centric” view of our interactions with our resident microbiota. As aptly described by Jorge Galán (Yale University) in the plenary session “Molecular Basis of Microbial–Immune Interactions,” pathogens are continually coevolving with our immune system and finding new ways to prevent or exploit inflammatory responses designed to promote their elimination. Even bacteria traditionally viewed as “commensal” may change their behavior in ways that promote their survival to our detriment, particularly in combination with host genetic predispositions and environmental pressures in the form of, for example, sanitation, vaccination, and antibiotic use. It is also well to remember the prescient admonition of Louis Pasteur: “C’est les microbes qui auront le dernier mot” (the microbes will have the last word).

Charlotte Slayton Kaetzel, Associate Editor