Gut 2012 Commentary

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Bifidobacteria and subsets ofdendritic cells: friendly playersin immune regulation!

Corinne Grangette

The mammalian gastrointestinal tractharbours a vast number of bacterial resi-dents, recently referred to as the micro-biota, which are instrumental insupporting energy metabolism andimmune function of the host. A largenumber of studies have highlighted thefact that certain (pathogenic) micro-organisms can be harmful to the health of

their host, while more recently anincreasing number of papers have attrib-uted direct beneficial health effects to thegut microbial community. As thesebacteria encode 100 times more genes thanpresent in the human genome, the part-nership of the host with its microbiotaconstitute a superorganism.1 Homoeo-stasis in this superorganism is sustainedthrough an optimal cohabitation of thehost with this microbiota, keeping thebalance between commensals and patho-gens, but also between proinflammatory

and regulatory responses. The compositionof the gut microbiota has indeed beenshown to be an important determinant ofTh17:Treg balance and may thus influenceintestinal immunity and tolerance.2

Disturbing alterations in the compositionof the microbiota (a process known asdysbiosis) will compromise such homoeo-stasis and promote the development ofvarious inflammatory disorders, such asinflammatory bowel disease. An in-depthunderstanding of the mechanisms under-lying hostesymbiont relationships will bepivotal for the development of new thera-

peutic or prophylactic interventionstargeting the intestinal microbiota.

One such approach is the use of probi-otics, mainly lactobacilli and bifidobac-teria, to impact on the host immunesystem. Depending on the strain, probi-otics may exert beneficial effects byaltering gut microbial diversity, improvingthe intestinal barrier or modulating the

hosts immune responses. By modulatingimmunological functions of dendritic cells(DCs), certain probiotics seem able topromote T helper 1 (Th1) responses,3

while others have clearly been shown toinduce tolerogenic DCs and regulatory T(Treg) responses.4e6 Unfortunately, notmuch is known about the host microbecross-talk which initiates these processes,

nor about the conditions that will sustain,promote or inhibit such effects. DCs playa fundamental role in the homoeostasis ofthe gut by orchestrating the balancebetween immunity and tolerance.

Two distinct subsets of DCs have nowbeen defined in the gut on the basis of theexpression of mutually exclusive markers,the integrin CD103 and the fractalkinereceptor CX3CR1.7 Only the CD103+CX3CR1 subset can migrate from thelamina propria (LP) to the mesentericlymph nodes to present locally adminis-

tered antigen to naive CD4 T cells. Theimmigrating CD103 LP DCs imprint guthoming molecules on T and B cells, andhave been shown to drive the differentia-tion of Tregs, via a mechanism mediatedby retinoic acid (RA) and transforminggrowth factor b, in contrast to CX3CR1DCs which drive the development of Thelper 17 (Th17) cells. Recently, it hasbeen shown that CD103 but not CD103gut DCs produce indoleamine 2, 3-dioxy-genase (IDO), an immunosuppressivepathway involved in tolerogenic func-tions.8 IDO-competent plasmacytoid DCs

(PDCs) are also known to be pivotalregulators of T cell responses at sites ofinflammation and IDO emerges also asa key molecular switch controlling thebalance between regulator and effectorfunctions of T cells.

In their paper published in Gut,Koniecznia and colleagues9 have conductedan in-depth study that deciphers themolecular mechanisms involved in theinduction of regulatory responses by strain

Bifidobacterium infantis 35624 (see page354). After confirming in humans that oral

consumption of this bacterium led to anenhanced interleukin (IL)-10 secretion and

Foxp3 expression in peripheral blood, theauthors studied how this probiotic strainmodulated DC functions to prime Tregs.Interestingly, they showed that thedifferentDC subsets useddifferentpattern-recognition receptors and molecular path-ways to induce Foxp3 T cells. Monocyte-

derived DCs (MDDCs), primary myeloidDCs (MDCs) and PDCs secreted IL-10 butnot IL-12p70, in response to B infantis, incontrast to unrelated bifidobacteria orpathogens, which induced both cytokines.Interestingly, inductionof FoxP3 Tcells andrelease of IL-10 by MDDCs and MDCsrequired the activation of the RA metabo-lism, TLR2 and DC-SIGN signalling, whileIDO and TLR9 were involved in inducinga regulatory profile in PDCs (figure 1). Incontrast, the other bifidobacteria evaluatedwere not able to induce expression of

Aldh1A2 (a gene involved in RA metabo-

lism) in MDDCs, but rather induced theexpression of T-bet (a critical transcriptionfactor forTh1 response) in autologous CD4Tcells co-cultured with theMDDCs. Theseresults therefore confirm the strain-specificimmune-modulation capacity of selectedprobiotic bacteria and provide molecularevidence of theirdifferentialcross-talkwithDCs.

Previous work has reported that PDCsare the dominant forms in the LP and thePeyers patches of C57BL/10 mice,whereas MDCs were the prevailing type

in the mesenteric lymph nodes. Bothtypes of DCs, however, express heteroge-neous phenotypes in the intestinalmucosa. The administration of the probi-otic mixture VSL#3 was shown to lowerthe proportion of PDCs within the LP by60%, whereas the PDC subset in themesenteric lymph nodes was more than200% higher than in control mice. Incontrast, the MDC number was higherthan the control in all intestinal lymphoidtissue compartments of the VSL#3-treatedmice.10 It is now clear that probioticadministration can modify the distribu-

tion, the phenotype and function of DCsubsets. The study by Koniecznia andcolleagues9 was performed in vitro, usingMDDCs or primary DCs derived fromhuman blood. It remains important toconfirm these results at the mucosal leveland to decipher there the respective acti-vation of the IDO and RA pathways inthe different DC subsets. The capacity ofselected lactobacilli to protect mice fromcolitis was recently shown to be linked totheir cell wall structure and to correlatewell with the induction of regulatory

pathways, including IDO activation

11

andwith the expansion of mucosal CD103

Correspondence to Dr Corinne Grangette, Lactic AcidBacteria and Mucosal Immunity, Center for Infection andImmunity of Lille, INSERM U1019 - CNRS UMR 8204,

Institut Pasteur of Lille, 1 rue du Pr Calmette, F59019Lille Cedex, 59000 Lille, France; [email protected]

Gut March 2012 Vol 61 No 3 331

Commentary

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DCs.12

Such micro-organisms can appar-ently exert immune regulatory effectsthrough the sensing of different bacterialcompounds by pattern-recognition recep-tors of the host. Attempts to furtherunderstand how they interact with theimmune system and drive respectivelyeffector or regulatory responses, willundoubtedly yield important informationon how to improve the selection of themost suitable strains for future thera-

peutic or prophylactic applications in, forexample, inflammatory bowel disease orother immune disorders.

Funding CG is supported by the Institut Pasteur of Lille,by lAssociation Francois Aupetit and by INSERM.

Competing interests None.

Provenance and peer review Not commissioned;externally peer reviewed.

Published Online First 1 December 2011

Gut2012;61:331e332. doi:10.1136/gutjnl-2011-301476

REFERENCES1. Eberl G. A new vision of immunity: homeostasis

of the superorganism. Mucosal Immunol2010;3:450e60.

2. Ivanov II, Frutos Rde L, Manel N, et al. Specificmicrobiota direct the differentiation of IL-17-producingT-helper cells in the mucosa of the small intestine.

Cell Host Microbe 2008;4:337e49.3. Mohamadzadeh M, Olson S, Kalina WV, et al.

Lactobacilli activate human dendritic cells that skewT cells toward T helper 1 polarization. Proc Natl AcadSci U S A 2005;102:2880e5.

4. Di Giacinto C, Marinaro M, Sanchez M, et al.Probiotics ameliorate recurrent Th1-mediated murinecolitis by inducing IL-10 and IL-10-dependentTGF-beta-bearing regulatory cells. J Immunol2005;174:3237e46.

5. Kwon HK, Lee CG, So JS, et al. Generation ofregulatory dendritic cells and CD4+Foxp3+ T cellsby probiotics administration suppresses immune

disorders. Proc Natl Acad Sci U S A2010;107:2159e64.

6. OMahony C, Scully P, OMahony D, et al.Commensal-induced regulatory T cells mediateprotection against pathogen-stimulated NF-kappaB

activation. PLoS Pathog 2008;4:e1000112.7. Schulz O, Jaensson E, Persson EK, et al.Intestinal CD103+, but not CX3CR1+, antigensampling cells migrate in lymph and serve classicaldendritic cell functions. J Exp Med2009;206:3101e14.

8. Matteoli G, Mazzini E, Iliev ID, et al. GutCD103+ dendritic cells express indoleamine2,3-dioxygenase which influences T regulatory/Teffector cell balance and oral tolerance induction.Gut 2010;59:595e604.

9. Koniecznia P, Groeger D, Ziegler M, et al.

Bifidobacterium infantis 35624 administration inducesFoxp3 T regulatory cells in human peripheral blood:potential role for myeloid and plasmacytoid dendriticcells. Gut 2012;61:354e66.

10. Wang X, OGorman MR, Bu HF, et al. Probiotic

preparation VSL#3 alters the distribution andphenotypes of dendritic cells within the intestinalmucosa in C57BL/10J mice. J Nutr2009;139:1595e602.

11. Foligne B, Zoumpopoulou G, Dewulf J, et al. A keyrole of dendritic cells in probiotic functionality. PLoSOne 2007;2:e313.

12. Macho Fernandez EM, Valenti V, Rockel C, et al.Anti-inflammatory capacity of selected lactobacilliin experimental colitis is driven by NOD2-

mediated recognition of a specificpeptidoglycan-derived muropeptide. Gut2011;60:1050e9.

Figure 1 Different dendritic cell (DC) subsets use different pattern-recognition receptors andmolecular pathways to induce Foxp3 regulatory T cells in response to Bifidobacterium 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 ofinterleukin (IL)-10, while plasmacytoid DCs (PDCs) require indoleamine 2, 3-dioxygenase (IDO) andTLR-9 signalling.

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doi: 10.1136/gutjnl-2011-3014762012 61: 331-332 originally published online December 1, 2011Gut

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

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