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Commentary

Bidobacteria and subsets of dendritic cells: friendly players in immune regulation!

Corinne Grangette
The mammalian gastrointestinal tract harbours a vast number of bacterial residents, recently referred to as the microbiota, which are instrumental in supporting energy metabolism and immune function of the host. A large number of studies have highlighted the fact that certain (pathogenic) microorganisms can be harmful to the health of their host, while more recently an increasing number of papers have attributed direct benecial health effects to the gut microbial community. As these bacteria encode 100 times more genes than present in the human genome, the partnership of the host with its microbiota constitute a superorganism.1 Homoeostasis in this superorganism is sustained through an optimal cohabitation of the host with this microbiota, keeping the balance between commensals and pathogens, but also between proinammatory and regulatory responses. The composition of the gut microbiota has indeed been shown to be an important determinant of Th17:Treg balance and may thus inuence intestinal immunity and tolerance.2 Disturbing alterations in the composition of the microbiota (a process known as dysbiosis) will compromise such homoeostasis and promote the development of various inammatory disorders, such as inammatory bowel disease. An in-depth understanding of the mechanisms underlying hostesymbiont relationships will be pivotal for the development of new therapeutic or prophylactic interventions targeting the intestinal microbiota. One such approach is the use of probiotics, mainly lactobacilli and bidobacteria, to impact on the host immune system. Depending on the strain, probiotics may exert benecial effects by altering gut microbial diversity, improving the intestinal barrier or modulating the hosts immune responses. By modulating immunological functions of dendritic cells (DCs), certain probiotics seem able to promote T helper 1 (Th1) responses,3 while others have clearly been shown to induce tolerogenic DCs and regulatory T (Treg) responses.4e6 Unfortunately, not much is known about the host microbe cross-talk which initiates these processes, nor about the conditions that will sustain, promote or inhibit such effects. DCs play a fundamental role in the homoeostasis of the gut by orchestrating the balance between immunity and tolerance. Two distinct subsets of DCs have now been dened in the gut on the basis of the expression of mutually exclusive markers, the integrin CD103 and the fractalkine receptor CX3CR1.7 Only the CD103+ CX3CR1 subset can migrate from the lamina propria (LP) to the mesenteric lymph nodes to present locally administered antigen to naive CD4 T cells. The immigrating CD103 LP DCs imprint gut homing molecules on T and B cells, and have been shown to drive the differentiation of Tregs, via a mechanism mediated by retinoic acid (RA) and transforming growth factor b, in contrast to CX3CR1 DCs which drive the development of T helper 17 (Th17) cells. Recently, it has been shown that CD103 but not CD103 gut DCs produce indoleamine 2, 3-dioxygenase (IDO), an immunosuppressive pathway involved in tolerogenic functions.8 IDO-competent plasmacytoid DCs (PDCs) are also known to be pivotal regulators of T cell responses at sites of inammation and IDO emerges also as a key molecular switch controlling the balance between regulator and effector functions of T cells. In their paper published in Gut, Koniecznia and colleagues9 have conducted an in-depth study that deciphers the molecular mechanisms involved in the induction of regulatory responses by strain Bidobacterium infantis 35624 (see page 354). After conrming in humans that oral consumption of this bacterium led to an enhanced interleukin (IL)-10 secretion and

Correspondence to Dr Corinne Grangette, Lactic Acid Bacteria and Mucosal Immunity, Center for Infection and Immunity of Lille, INSERM U1019 - CNRS UMR 8204, Institut Pasteur of Lille, 1 rue du Pr Calmette, F59019 Lille Cedex, 59000 Lille, France; corinne.grangette@ibl.fr Gut March 2012 Vol 61 No 3

Foxp3 expression in peripheral blood, the authors studied how this probiotic strain modulated DC functions to prime Tregs. Interestingly, they showed that the different DC subsets used different patternrecognition receptors and molecular pathways to induce Foxp3 T cells. Monocytederived DCs (MDDCs), primary myeloid DCs (MDCs) and PDCs secreted IL-10 but not IL-12p70, in response to B infantis, in contrast to unrelated bidobacteria or pathogens, which induced both cytokines. Interestingly, induction of FoxP3 Tcells and release of IL-10 by MDDCs and MDCs required the activation of the RA metabolism, TLR2 and DC-SIGN signalling, while IDO and TLR9 were involved in inducing a regulatory prole in PDCs (gure 1). In contrast, the other bidobacteria evaluated were not able to induce expression of Aldh1A2 (a gene involved in RA metabolism) in MDDCs, but rather induced the expression of T-bet (a critical transcription factor for Th1 response) in autologous CD4 Tcells co-cultured with the MDDCs. These results therefore conrm the strain-specic immune-modulation capacity of selected probiotic bacteria and provide molecular evidence of their differential cross-talk with DCs. Previous work has reported that PDCs are the dominant forms in the LP and the Peyer s patches of C57BL/10 mice, whereas MDCs were the prevailing type in the mesenteric lymph nodes. Both types of DCs, however, express heterogeneous phenotypes in the intestinal mucosa. The administration of the probiotic mixture VSL#3 was shown to lower the proportion of PDCs within the LP by 60%, whereas the PDC subset in the mesenteric lymph nodes was more than 200% higher than in control mice. In contrast, the MDC number was higher than the control in all intestinal lymphoid tissue compartments of the VSL#3-treated mice.10 It is now clear that probiotic administration can modify the distribution, the phenotype and function of DC subsets. The study by Koniecznia and colleagues9 was performed in vitro, using MDDCs or primary DCs derived from human blood. It remains important to conrm these results at the mucosal level and to decipher there the respective activation of the IDO and RA pathways in the different DC subsets. The capacity of selected lactobacilli to protect mice from colitis was recently shown to be linked to their cell wall structure and to correlate well with the induction of regulatory pathways, including IDO activation11 and with the expansion of mucosal CD103
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Commentary
REFERENCES
1. Eberl G. A new vision of immunity: homeostasis of the superorganism. Mucosal Immunol 2010;3:450e60. Ivanov II, Frutos Rde L, Manel N, et al. Specic microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008;4:337e49. Mohamadzadeh M, Olson S, Kalina WV, et al. Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization. Proc Natl Acad Sci U S A 2005;102:2880e5. Di Giacinto C, Marinaro M, Sanchez M, et al. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J Immunol 2005;174:3237e46. Kwon HK, Lee CG, So JS, et al. Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc Natl Acad Sci U S A 2010;107:2159e64. OMahony C, Scully P, OMahony D, et al. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation. PLoS Pathog 2008;4:e1000112. Schulz O, Jaensson E, Persson EK, et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med 2009;206:3101e14. Matteoli G, Mazzini E, Iliev ID, et al. Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which inuences T regulatory/T effector cell balance and oral tolerance induction. Gut 2010;59:595e604. Koniecznia P, Groeger D, Ziegler M, et al. Bidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells. Gut 2012;61:354e66. Wang X, OGorman MR, Bu HF, et al. Probiotic preparation VSL#3 alters the distribution and phenotypes of dendritic cells within the intestinal mucosa in C57BL/10J mice. J Nutr 2009;139:1595e602. Foligne B, Zoumpopoulou G, Dewulf J, et al. A key role of dendritic cells in probiotic functionality. PLoS One 2007;2:e313. Macho Fernandez EM, Valenti V, Rockel C, et al. Anti-inammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2mediated recognition of a specic peptidoglycan-derived muropeptide. Gut 2011;60:1050e9.

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Figure 1 Different dendritic cell (DC) subsets use different pattern-recognition receptors and molecular pathways to induce Foxp3 regulatory T cells in response to Bidobacterium infantis: monocyte-derived DCs (MDDCs) and myeloid DCs (MDCs) require T cell receptor-2 (TLR-2), DC-SIGN and retinoic acid (RA) metabolism for the induction of Foxp3 T cells and the release of interleukin (IL)-10, while plasmacytoid DCs (PDCs) require indoleamine 2, 3-dioxygenase (IDO) and TLR-9 signalling. DCs.12 Such micro-organisms can apparently exert immune regulatory effects through the sensing of different bacterial compounds by pattern-recognition receptors of the host. Attempts to further understand how they interact with the immune system and drive respectively effector or regulatory responses, will undoubtedly yield important information on how to improve the selection of the most suitable strains for future therapeutic or prophylactic applications in, for example, inammatory bowel disease or other immune disorders.
Funding CG is supported by the Institut Pasteur of Lille, by lAssociation Franc ois Aupetit and by INSERM. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. Published Online First 1 December 2011 Gut 2012;61:331e332. doi:10.1136/gutjnl-2011-301476

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Gut March 2012 Vol 61 No 3

Downloaded from gut.bmj.com on April 10, 2012 - Published by group.bmj.com

Bifidobacteria and subsets of dendritic cells: friendly players in immune regulation!

Corinne Grangette Gut 2012 61: 331-332 originally published online December 1, 2011

doi: 10.1136/gutjnl-2011-301476

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