MUCOSAL IMMUNITY Tuftcells,taste-chemosensorycells ... · MUCOSAL IMMUNITY Tuftcells,taste-chemosensorycells, orchestrate parasite type 2 immunity in the gut Michael R. Howitt, 1Sydney

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E4530–E4539 (2013).

ACKNOWLEDGMENTS

We thank V. Funari for assistance with RNA sequencing,A. Cammack for assisting with patient tissue, and A. Koehne for

assisting with pathology evaluation. This work was supported byNIH grants NS069669 (R.H.B), NS087351 (C.M.L), GM085796(D.M.U.), NS078398 (T.M.M.), and UL1TR000124; the Robertand Louise Schwab family; the Cedars-Sinai ALS Research Fund(R.H.B.); and the Cedars-Sinai Board of Governors RegenerativeMedicine Institute. T.M.M. has served on medical advisoryboards for Ionis Pharmaceuticals and Biogen Idec. Mouse lineF12 is available through the Jackson Repository, no. 27068, C57BL/6J-3110043O21Rik<em5Lutzy>/J. RNA-seq data are located in theGene Expression Omnibus, accession number GSE77681.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/351/6279/1324/suppl/DC1Materials and MethodsSupplementary TextFigs. S1 to S11Data Tables S1 and S2

20 December 2015; accepted 9 February 201610.1126/science.aaf1064

MUCOSAL IMMUNITY

Tuft cells, taste-chemosensory cells,orchestrate parasite type 2 immunityin the gutMichael R. Howitt,1 Sydney Lavoie,1 Monia Michaud,1 Arthur M. Blum,2 Sara V. Tran,3

Joel V. Weinstock,2 Carey Ann Gallini,1 Kevin Redding,3 Robert F. Margolskee,3

Lisa C. Osborne,4* David Artis,4 Wendy S. Garrett1,5,6†

The intestinal epithelium forms an essential barrier between a host and itsmicrobiota. Protozoaand helminths aremembers of the gutmicrobiota ofmammals, including humans, yet themanyways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear.Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate duringparasite colonization and infection. Disruption of chemosensory signaling through the loss ofTRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoidcells during parasite colonization.Tuft cells are the primary source of the parasite-inducedcytokine interleukin-25,which indirectly induces tuft cell expansion by promoting interleukin-13production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinelsin the gut epithelium that promote type 2 immunity in response to intestinal parasites.

The mammalian gut microbiota is a collec-tive of bacteria, archaea, viruses, fungi, andparasites that reside in the lumen and mu-cosal surface of the intestine. Thesemicrobesare sequestered from interior tissues by a

single layer of epithelial cells lining the gut thatacts as a barrier and sensor. Intestinal epithelial

cells (IECs) express pattern recognition receptorsthat detect microbial components and thus arecritical sensors for and orchestrators of mucosalimmunity (1–4).Beyond pattern recognition receptors, hosts

monitor and respond to the microbiota via het-erotrimeric guanine nucleotide–binding protein(Gprotein)–coupled receptors (GPCRs). For exam-ple,microbially produced short-chain fatty acidsare sensed via GPR41 and GPR43 (5, 6), and sino-nasal epithelial cells can detect the pathogenPseudomonasaeruginosa via a taste-chemosensoryGPCR (7–12). Many taste-chemosensory GPCRsrequire the taste-specificGproteinsubunitgustducinand the cation channel TRPM5 to transduce theirsignals (7, 9). The disruption of either gustducinor TRPM5 can perturb physiological responsesto P. aeruginosa (13–15). In the gut, TRPM5 andother canonical taste-chemosensory componentsare predominantly expressed by an intestinal epi-thelial subset called tuft cells (16). Tuft cells, which

are identified by the expression of doublecortin-like kinase 1 (DCLK1), comprise a minor frac-tion of small intestinal epithelial cells (17–19) andare putative quiescent stem cells (20). Althoughtuft cells express taste-chemosensory machin-ery, it is unknown whether tuft cells sense thegut microbiota by means of taste chemosensa-tion or transduce signals to themucosal immunesystem (21).Webeganby evaluating the frequencyofDCLK1+

tuft cells in the distal small intestine of wild-type(WT) specific-pathogen-freemice thatwere bredin-house (BIH).We foundmarkedlymore intesti-nal DCLK1+ tuft cells (7.2%) (Fig. 1A) than previousreports (0.4%) (19, 22) and confirmed this discrep-ancy with an alternative tuft cell marker, GFI1B(fig. S1) (23). As interinstitutional differences inmicrobiota can contribute to substantial variationamongmucosal immune cell populations (24), wecompared tuft cell abundance in mice obtainedfrom The Jackson Laboratory (JAX) with BIHmice. Similar to previous reports (19, 25), tuft cellsconstituted 1.0% of the total IEC population ofJAXmice (Fig. 1A). Feeding the cecal contents fromBIHmice to JAXmice was sufficient to increasetuft cell populations to BIH levels (fig. S2), suggest-ing that transmissible components of the BIHmicrobiota may drive tuft cell expansion whenintroduced to JAX mice. In support of this idea,intestinal histology revealed numerous single-celled protozoa in BIH but not in JAX mice (Fig.1B). To identify these protozoa, we purified andimaged them by means of scanning electronmicroscopy (SEM); we identified them as tritricho-monads (Fig. 1C) (26–28). Quantitative polymerasechain reaction (qPCR) confirmed that they wereTritrichomonasmuris (Tm), a commonbutunder-studiedmember of the rodentmicrobiota (Fig. 1D).To eradicate Tm fromBIHmice, we addedmet-

ronidazole (2.5 g/liter) to their drinkingwater for1 week. This eliminated Tm and concomitantlyreduced tuft cell abundance (fig. S3). Because thistreatment does not exclude the possibility thatothermetronidazole-sensitive organismsmay con-tribute to tuft cell expansion, we cultured Tm(28, 29) and colonized unexposedmice. Tm colo-nization significantly elevated tuft cell numbers in

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1Departments of Immunology and Infectious Diseases and Geneticsand Complex Diseases, Harvard T. H. Chan School of Public Health,Boston, MA 02115, USA. 2Division of Gastroenterology, TuftsMedical Center, Boston, MA 02111, USA. 3Monell ChemicalSenses Center, Philadelphia, PA 19104, USA. 4Jill RobertsInstitute for Research in Inflammatory Bowel Disease, WeillCornell Medical College, Cornell University, New York, NY 10021,USA. 5Broad Institute of Harvard and Massachusetts Institute ofTechnology, Cambridge, MA 02142, USA. 6Department ofMedical Oncology, Dana-Farber Cancer Institute, Boston, MA02215, USA.*Present address: Department of Microbiology and Immunology,University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada. †Corresponding author. E-mail: [email protected]

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conventional (Fig. 1, E and F) and germ-freemice(fig. S4), suggesting that this symbiotic protozoais sufficient to increase tuft cell frequency.Helminths are common eukaryotic inhabitants

of the mammalian intestine, but they are evolu-tionarily distinct from protozoa. These parasitesinflict a substantial global health burden, yetwormsmay also provide therapeutic benefits (8).To investigate the effect of helminth infection ontuft cell abundance, we infectedmicewith a diverseset of parasitic worms including Heligmosomoidespolygyrus (Hp), Trichinella spiralis (Ts), andNippostrongylus brasiliensis (Nb). Similar to ourresults with Tm, infections with all three hel-minths increased tuft cell abundance, indicatingthat expansion of tuft cells is a broadly conservedfeature of parasite colonization (Fig. 1, G and H).Because tuft cells are postulated to be chemo-

sensory cells (30), we consideredwhether pertur-bations to tuft chemosensory pathwaysmay affecttheir expansion in response to parasites and/or tothe type 2 immune response typically initiated byparasites. Multiple taste-chemosensory GPCRssense sweet, bitter, and umami compounds; en-gagement of these different receptors activates acommon signal transduction pathway involving

gustducin, PLCb2, and TRPM5 (Fig. S5) (7, 9).We confirmed that GFI1B+ tuft cells are the pri-mary IEC subset expressing the canonical taste-associated components gustducin, PLCb2, andTRPM5 (Fig. 2A) (16, 23, 31).We compared tuft cell abundance in WT and

gustducin-deficient (gustducin−/−) mice colonizedwith Tmand found significantly fewer tuft cells ingustducin−/− animals (Fig. 2B). Using Trpm5eGFP

(eGFP, enhanced green fluorescent protein) re-portermice,we validated that TRPM5 is restrictedto the epithelium and expressed by DCLK1+ tuftcells in the distal small intestine (Fig. 2C and fig.S6). Given themultiplicity of taste-chemosensoryGPCRs, the established role of TRPM5 in tastechemosensation (7, 32), and the predominant in-testinal TRPM5 expression by tuft cells, we usedTRPM5-deficient mice to evaluate whether thesepathways affect tuft cell parasite responses. Similarto gustducin−/−mice, tuft cells failed to expand inTrpm5−/−mice during Tm colonization (Fig. 2, Dto F). To determine whether the blunted responsewas due to reduced parasite colonization, wemea-sured Tm in the distal small intestine (fig. S7A).Wefound slightlymore parasites in both gustducin−/−

and Trpm5−/− mice than in WT mice (fig. S7B),

indicating that the lack of tuft cell response wasnot due to decreasedTmcolonization. Because Tmis a stable component of themicrobiota, we testedhow the loss of TRPM5would affect clearance ofa pathogenic helminth such asHp. Thirty-six daysafter infection, we determined that Trpm5−/−micehad a significantly higher wormburden thanWTmice (fig. S7C). Collectively, these data suggest thatpathways initiated upstream of TRPM5 may me-diate tuft cell responses to intestinal parasites.If tuft cell responses represent an early step in

parasite recognition, we hypothesized that otherantiparasitic responsesmay be altered in parasite-burdenedTrpm5−/−mice. Consistentwithhelminthinfections (33), Tm colonization also induced gob-let cell hyperplasia inWT (P < 0.0001) but not inTrpm5−/− mice (Fig. 2, G and H). Similarly, weobserved eosinophilia inWT but not in Trpm5−/−

mice colonized with Tm (Fig. 2I).Because epithelial cells are a key source of the

parasite-induced cytokines thymic stromal lym-phopoietin (TSLP) and interleukin-33 (IL-33) and-25 (17), we isolated tuft cells and the remainingepithelial fraction to determine TSLP, IL-33, andIL-25 expression patterns. Consistent with recentreports, we found that tuft cells expressed less

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Fig. 1. Symbiotic protozoa or helminths increaseintestinal tuft cell abundance. (A) DCLK1+ tuftcell frequency in the small intestine (SI) of WT BIHand WT JAX mice. (B) Hemtoxylin and eosin–stained SI sections fromWT BIH and WTJAX mice(scale bar, 50 mm) (left). A higher magnification ofthe WT BIH section is shown on the right (scale bar,20 mm). (C) SEM micrograph of protozoa isolatedfrom WT BIH mice (scale bar, 4 mm). (D) Tm abun-dance in stool DNA (Tm 28S rRNA relative to Eu-bacteria 16S rRNA), determined by qPCR (ND, notdetectable). (E) Representative SI images from un-infected and Tm-colonized mice and (F) tuft cellfrequency. (G) Representative SI images from un-infected and helminth-colonized mice and (H) tuftcell frequency. DCLK1 is shown in green, E-cadherinin red, and DAPI (4′,6-diamidino-2-phenylindole) inblue [scale bars in (E) and (G), 100 mm]. Each sym-bol represents an individual mouse, and all data arerepresentative of two [(D), (F), and (H)] or three(A) independent experiments. Tm infection was17 days in (E) and (F). In (G) and (H), Hp infectionwas 21 days, Ts infection was 15 days, and Nb in-fection was 8 days. Data are plotted as means withSD. Four stars, P < 0.0001; three stars, P = 0.0001;one-way analysis of variance (ANOVA) or Mann-Whitney test.

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TSLP and IL-33 than other epithelial cells and arethe main source of epithelial IL-25 (Fig. 3A andfig. S8A) (34, 35). To determine whether TRPM5 af-fects parasite-induced IL-25 expression,we infectedWT and Trpm5−/− mice with Tm and measuredboth parasite colonization and the correspondingepithelial IL-25 expression over time. Tm rapidlycolonized both WT and Trpm5−/− mice, butTrpm5−/− mice had significantly reduced IL-25expression 12 days after infection (P = 0.0006)(Fig. 3B).IL-25 promotes proliferation and activation of

type 2 innate lymphoid cells (ILC2s) via the recep-tor subunit IL17RB (11, 36, 37). Accordingly, the fre-quency of intestinal lamina propria IL17RB+ ILC2ssignificantly increased in WT but not Trpm5−/−

mice after 12 days of Tm infection (Fig. 3C). To de-terminewhether theparasite response inTrpm5−/−

mice could be complemented by exogenous IL-25,

we injected IL-25 intraperitoneally into Trpm5−/−

mice; we observed restoration of distal small in-testinal eosinophilia and tuft cell abundance (Fig. 3,D to F), suggesting that tuft cells may influencetheir own abundance.Epithelial cells are not only a crucial source of

IL-25 but also signal in an autocrine manner viaIL17RB (22). Therefore, we examined tuft cellIL17RB expression and found that it was signif-icantly higher (P= 0.0043) than for other epithelialcells (fig. S8B). This raised the question of whetherIL-25 induces tuft cell expansion via autocrinesignaling or indirectly through recruitment ofILC2s. To evaluate factors that affect tuft cellabundance independently of the microbiota orimmune system, we used an in vitro primary in-testinal organoid system (38, 39). Small intestinalorganoids reconstitute all the epithelial subsetsfrom IEC stem cells. By generating organoids from

Gfi1beGFP/+ mice, we detected GFP+ tuft cells(Fig. 4A and fig. S9A). Both WT and Trpm5−/−

organoids contained ~0.3% tuft cells, but IL-25did not increase tuft cell numbers (Fig. 4B andfig. S9A), suggesting that IL-25 does not act in anautocrine manner to expand tuft cell abundance.Because IL-25promotes expansionof ILC2s,whichare critical sources of IL-13 (11, 36, 40), a cytokinepreviously shown to increase goblet cell numbers(25), we considered that IL-13 may also increasetuft cell abundance. IL-13 significantly expandedtuft cells from 0.3% of total organoid cells to 11.9%and 10.9% (WT and Trpm5−/−, respectively) (Fig.4B and fig. S9A). In agreementwith these results,expression of DCLK1 and TRPM5 also increasedin IL-13–treated organoids (fig. S9, B and C).To determine whether type 2 cytokine produc-

tion by ILC2s may contribute to tuft cell expan-sion in vivo, we colonizedWT, Stat6−/−, Rag2−/−,

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Fig. 2.Tuft cells influence type 2 immunity through TRPM5. (A) Gustducin,PLCb2, and TRPM5 expression in sorted tuft cells, compared with the non–tuftcell epithelium. (B) Representative images of Tm-colonized WTand gustducin−/−

mice and tuft cell frequencies. (C) Representative image from Trpm5eGFP mice.GFP is shown in green), DCLK1 in red), DAPI in blue, and phalloidin in white.(D) Representative image of Tm-colonized Trpm5−/− mice and tuft cell fre-quencies. Scale bars in (B), (C), and (D), 50 mm. (E) Representative flowcytometry plots of IECs from uninfected (left) or Tm-colonized (right) WT(Gfi1beGFP/+, top) and Trpm5−/− (Gfi1beGFP/+ Trpm5−/−, bottom) mice and

(F) tuft cell frequency. (G) Goblet cells in SI sections stainedwith Alcian blueand nuclear red in uninfected WTand Tm-colonized WTand Trpm5−/− miceand (H) goblet cell frequency. (I) Eosinophil frequency in the distal SI laminapropria (LP) of uninfected and Tm-colonized WTand Trpm5−/− mice. Scalebars, 50 mm. Each symbol represents an individual mouse, and all dataare representative of at least three independent experiments. Data areplotted as means with SD. Four stars, P < 0.0001; three stars, P = 0.0001;two stars, P < 0.01; ns, not significant; one-way ANOVA, Kruskal-Wallis, orMann-Whitney tests.

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Fig. 3. Tuft cells express IL-25 and elicit ILC2s in aTRPM5-dependent manner in response to symbioticprotozoa. (A) IL-25 expression from sorted tuft cells.(B)WT (solid circles) and Trpm5−/− (open circles)mice

were colonized with Tm for 3, 7, 12, and 42 days. At each time point, epithelial cell IL-25 expression was measured (purple line) and Tm colonization wasquantified (green line). (C) Frequencyof IL17RB+ (IL-25R) ILC2s in the distal SI LPof uninfectedWTmice andWTandTrpm5−/−mice colonizedwith Tm for 12 days.(D) Eosinophil frequency in the distal SI LP of uninfected WTor Tm-colonized Trpm5−/− mice intraperitoneally injected with IL-25 or phosphate-buffered saline(PBS) control. (E) Tuft cell frequencies and (F) flow plots of epithelial cells isolated fromTrpm5−/−mice intraperitoneally injectedwith IL-25 or PBS. Each symbol in(C), (D), and (E) represents an individualmouse, and all data are representative of three independent experiments. Data are plotted asmeanswith SD.Three stars,P < 0.001; two stars, P < 0.01; Kruskal-Wallis or Mann-Whitney tests.

Fig. 4. Innate lymphoid cells and IL-13 increase tuft cells in organoidsand the small intestine. (A) Differential interference contrast, fluores-cent, and merged images of small intestinal organoids generated fromGfi1beGFP/+ mice (scale bars, 25 mm). (B) GFP+ tuft cell abundance byflow cytometry of WTand Trpm5−/− organoids treated with recombinantIL-13 or IL-25. (C) Representative images of SI from WT, Stat6−/−, Rag2−/−,

and Rag2−/−Il2rg−/− mice colonized with Tm and (D) tuft cell frequency.DCLK1 is shown in green, E-cadherin in red, and DAPI in blue (scale bars,100 mm). Each symbol in (D) represents an individual mouse, and all dataare representative of (D) two or (B) three independent experiments. Dataare plotted as means with SD. Four stars, P < 0.0001; one-way ANOVA orMann-Whitney tests.

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and Rag2−/−Il2rg−/− mice with Tm (fig. S10).STAT6 is activated by the type 2 cytokines IL-4and IL-13 and is required for intestinal helminthexpulsion (26). Consistent with our organoid datademonstrating that IL-13 potently induces tuftcell expansion, tuft cells did not expand when Tmcolonized Stat6−/− mice (Fig. 4, C and D). Al-though both T helper 2 (TH2) and ILC2 cells canproduce IL-13 in mucosal tissue (41), parasite-induced IL-25 potently activates IL-13 expressionin ILCs (11, 36, 42). We compared tuft cell abun-dance in Rag2−/− mice that lack TH2 cells butcontain ILC2s versus Rag2−/−Il2rg−/− mice thatlack both TH2 and ILC2s cells (8, 11, 12). InfectedRag2−/− mice had elevated tuft cell abundancecompared with uninfected WT mice; however,similar to both Trpm5−/− and Stat6−/− mice,Rag2−/−Il2rg−/− mice showed no tuft cell increaseduring Tm infection (Fig. 4, C andD). Collectively,these data suggest that tuft cells may detect Tmthrough TRPM5 taste chemosensation to elicitILCs, which in turn produce IL-13 to expand tuftcell abundance (fig. S11).IECs are positioned for direct contact with lu-

menal microbes andmicrobial products, and theyfunction as sensory nodes to promote homeosta-sis with symbioticmicrobes and initiate immunityagainst pathogens. Eukaryota, including helminthsand protozoa, are common members of the gutmicrobiota (43, 44) that profoundly modulatethe host immune system (45, 46). Many of the pat-tern recognition receptor systems that recognizebacterial members of the microbiota do not con-tribute to recognition of parasites (47, 48). Herewe show that tuft cells orchestrate type 2 immu-nity, in agreementwith two recent studies (34, 35).Taste receptors respond to a panoply of ingestedagonists (18), and we speculate that tuft cells andtaste chemosensation within the gut provide sim-ilarly broad recognition of parasitic signals.

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ACKNOWLEDGMENTS

We thank members of the Garrett Lab for helpful discussion,T. Stappenbeck for supplying L-WRN cells, R. Montgomery forhelp with organoid imaging, and W. Fowle for help with SEM. Thedata from this study are tabulated in the main paper and in thesupplementary materials. Trpm5eGFP, Trpm5−/−, and gustducin−/−

mice are available from Monell Chemical Senses Center under amaterial transfer agreement. This work was supported by NIHNational Research Service Award (NRSA) F32DK098826 to M.R.H.;NIH NRSA F31DK105653 to S.L.; and NIH grants R01 CA154426and R01 GM099531, a Burroughs Wellcome Career in MedicalSciences Award, and a Searle Scholars Award to W.S.G. Theauthors declare no competing financial interests.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/351/6279/1329/suppl/DC1Materials and MethodsFigs. S1 to S13References (49–53)

24 September 2015; accepted 27 January 2016Published online 4 February 201610.1126/science.aaf1648

INFLAMMATION

Prostaglandin E2 constrains systemicinflammation through an innatelymphoid cell–IL-22 axisRodger Duffin,1 Richard A. O’Connor,1 Siobhan Crittenden,1 Thorsten Forster,2

Cunjing Yu,1 Xiaozhong Zheng,1 Danielle Smyth,3* Calum T. Robb,1 Fiona Rossi,4

Christos Skouras,1 Shaohui Tang,5 James Richards,1 Antonella Pellicoro,1

Richard B. Weller,1 Richard M. Breyer,6,7 Damian J. Mole,1 John P. Iredale,1

Stephen M. Anderton,1 Shuh Narumiya,8,9 Rick M. Maizels,3* Peter Ghazal,2,10

Sarah E. Howie,1 Adriano G. Rossi,1 Chengcan Yao1†

Systemic inflammation, which results from the massive release of proinflammatorymolecules into the circulatory system, is a major risk factor for severe illness, but theprecise mechanisms underlying its control are not fully understood. We observed thatprostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in humansystemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemicinflammation, associated with translocation of gut bacteria, which can be prevented bytreatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signalingacts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis anddriving them to produce interleukin-22 (IL-22). Disruption of the ILC–IL-22 axis impairsPGE2-mediated inhibition of systemic inflammation. Hence, the ILC–IL-22 axis isessential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling toimpede systemic inflammation.

Systemic inflammation commonly developsfrom locally invasive infection, is character-ized by dysregulation of the innate immunesystem and overproduction of proinflam-matory cytokines, and can result in severe

critical illness (e.g., bacteremia, sepsis, and septicshock) (1, 2). Despite much research on systemic

inflammation, our understanding of the precisemechanisms for its control remains incompleteand represents an unmet clinical need (1–3).Prostaglandins (PGs) are bioactive lipid media-tors generated from arachidonic acid via the en-zymatic activity of cyclooxygenases (COXs) (4). PGsparticipate in the pathogenesis of inflammatory

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Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut

Redding, Robert F. Margolskee, Lisa C. Osborne, David Artis and Wendy S. GarrettMichael R. Howitt, Sydney Lavoie, Monia Michaud, Arthur M. Blum, Sara V. Tran, Joel V. Weinstock, Carey Ann Gallini, Kevin

originally published online February 4, 2016DOI: 10.1126/science.aaf1648 (6279), 1329-1333.351Science 

, this issue p. 1329; see also p. 1264Scienceof mice to control a parasitic infection.chemosensory signaling machinery: disrupting this blocked parasite-triggered tuft cell expansion and weakened the abilityfor parasite clearance that also indirectly feeds back on tuft cells to expand their numbers. Tuft cells express parasites colonize or infect the gut. Parasites cause tuft cells to secrete large amounts of interleukin-25, a key cytokinetuft cells (see the Perspective by Harris). Tuft cells make up a small fraction of gut epithelial cells but expand when

now identify a key cellular player in immunity to parasites:et al.orchestrate parasite-targeted immune responses. Howitt Trillions of microbes inhabit our guts, including worms and other parasites. Epithelial cells that line the gut

Tuft cells help contain parasites

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REFERENCES

http://science.sciencemag.org/content/351/6279/1329#BIBLThis article cites 51 articles, 14 of which you can access for free

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