• Aucun résultat trouvé

Studies on the Tissue-Related Phenotypic Heterogeneity of Murine B Cells


Academic year: 2022

Partager "Studies on the Tissue-Related Phenotypic Heterogeneity of Murine B Cells"

En savoir plus ( Page)

Texte intégral


Developmental Immunology, 1998, Vol. 6, pp. 179-185 Reprintsavailabledirectlyfrom thepublisher Photocopying permitted bylicenseonly

(C)1998OPA (OverseasPublishersAssociation) N.V.Publishedbylicenseunder the HarwoodAcademicPublishers imprint, partoftheGordonandBreachPublishingGroup Printed inMalaysia

Studies on the Tissue-Related Phenotypic Heterogeneity of Murine B Cells







almmunological and BiotechnologicalLaboratory, University Medical SchoolofPdcs, Hungary;bDepartmentofDermatology, University Medical SchoolofDebrecen,Hungary

(Received 6August1996; Accepted 12August1997;Infinalform30September1997)

Thedevelopment ofB cells isaccompanied bytheirabilityto specificallyentertheperipheral lymphoid tissues. Recently, we described a novelrat monoclonal antibody (IBL-2; IgG2b/t0 reactingwith a26/29-kDheterodimeric structureof the cell surface. This mAb has been found torecognize differentiallytheperipheralB cellsof micedependingontheir tissueorigin.The majorityofsplenicBcellsaswell asthe matureB cells in the bone marrow were stained with this mAb, whereas the B lymphocytes isolated from LN or Peyer’s patches displayed only negligible reactivity.Weextendedthese observationsby analyzingtherelationshipbetween the expression ofIBL-2 antigen and L-selection on the surface of B-cell precursors in the bone marrowby multiparameterflowcytometry.WithintheB220 positive compartment,asignificant difference of L-selectin expression could be observed between the various IBL-2-reactive subsets. Furthermore, we investigated whether evidences for the establishment of tissue- associatedphenotypic heterogeneitysimilar tothat found innormalmicecould be foundupon theadoptivetransfer of normalunselected spleniclymphocytesintoSCIDrecipients(Spl-SCID).

Ithasbeen found that alarge part ofthesplenicBcellspreservedtheirIBL-2 reactivity,whereas theLN Bcellshad lost the IBL-2antigeninSpl-SCID.Thesedata indicate that thephenotypic difference withintheSCIDmicemaybe the result of themigrationofBlymphocytesfrom the spleentoward thelymph nodes,and the alteredexpressionof the IBL-2antigencorrelates with thisprocess.

Keywords: Bcells, spleen,bone marrow, L-selectin,IBL-2,SCID


The spleen is a major target organ for peripheral lymphocyte homing. Its histological architecture is rather complex, partly composed of erythromyeloid regions containing some migrating lymphoid ele-

Corresponding author.

ments. This red pulp is intermingled with lymphoid white pulp that, according to its cellular content, is further subdivided into T- and B-cell compartments (van Ewijk and Nieuwenhuis, 1985). This consider- able cellular and functionalheterogeneityhas signifi- cantly hampered the understanding of how the



180 PtTERBALOGHetal.

lymphocytes may localize to specific regions.

Whereas the splenicrecirculation kinetics ofboth the Tand B cells have beenthoroughlystudied (Stevens etal., 1982; Pabst andWestermann, 1991;Pickerand Butcher, 1992), little is known about the cellular interactions leading to their extravasation and sub- sequent tissuepositioning. Thesinus-liningcellsand, less likely, the marginal zone macrophages in the spleen have been reported to perform binding func- tions similar tothose ofHEVcells(Kraaletal., 1995;

Lyonsand Parish, 1995). However,theadhesionof of lymphocytes to either of these cells in the spleen appears to be independent of the L-selectin or c4/37 molecules, the characteristic leukocyte structures for binding to HEV in the lymph nodes and mucosal lymphoid tissues, respectively (Picker and Butcher, 1992; Bradley et al., 1994). It is worthwhile to mention that the splenic but not the bone marrow homing of myeloid precursors has proved to be independent of theinteractionsbetween the VCAM-1 and VLA-4 molecules (Papayannopoulou et al., 1995).

Thedetailsof thein situmigration oflymphocytes subsequent to the extravasation are also largely unknown. Itis supposedthat variouspolysaccharides produced by microenvironmental elements may con- tribute to the lymphoid organization of the spleen (Parish and Snowden, 1985; Kraal et al., 1994). On the other hand, it is not only the microenvironment that influences the lymphocyte migration, but the presence of certain lymphoid elements can also modulate the composition of the mesenchymal scaf- folding, according to the results obtained in SCID mice (Yoshida et al., 1993). Under normal circum- stances, the splenic entry of lymphocytes can be divided into two subsequent parts. The extravasation into the red pulp is independent from G-protein- coupledlymphocytemembranecomponentsinhibited by pertussis toxin (PTX), whereas the subsequent migration ofT andB lymphocytes from the redpulp toward the various compartments of white pulp is likely to be mediated by PTX-sensitive structures (Cyster and Goodnow, 1995). It is also not known whether what kind of phenotypic alterations take

placeinthelymphocytes upontheirsplenic lodgingor returnfrom the spleento thecirculation.

We have recently reported the isolation and characterization of a novel rat monoclonal antibody IBL-2. This mAb reacts with the mature B cells (identifiedaslg-positive cells)purified fromspleenor bone marrow, whereas the B cells from other peripheral lymphoidtissues were notrecognized. The T cells, including the splenic T cells, do not express the antigen (Balogh etal., 1992; Balogh and Kumfi- novics, 1995). Hereweextend these observations by investigating thecoexpressionofL-selectinandIBL- 2 antigensonB-cellprecursorsinthe bonemarrow.In addition,wereporttheresult of experimentsemploy- ing adoptivecell transfer of normal BALB/c splenic lymphocytesintoSCID recipients.These experiments wereaimed atconfirming the differential reactivity of peripheral B cells with IBL-2 mAb determined by their tissue location.


Coexpression of IBL-2 Antigen and L-Selectin on B-CellPrecursors in Bone Marrow

Our previous finding was that, employing anti- immunoglobulin antibodies as lineage marker, the reactivitypattern of splenicB cellswasquite similar tothat ofmarrowBcells. Themajorityof these cells ofeither sourcealso expressed L-selectin(Baloghet al., 1995). In order to determine the simultaneous expression of L-selectin and IBL-2 antigen on immature B-cellprecursors,wefirstdepletedthe bone marrow cells of cell-bearing Igontheirsurface. The residual cells were labeledwith an anti-B220 (RA3- 6B2), MEL-14, and IBL-2 mAbs. A representative example of these three-color stainings are shown in Figure 1.

Themajorityof theB220 cellsareIBL-2-negative (approximately 58%), whereas the rest are either weakly or strongly reactive with this mAb (approxi- mately 32% and 10%, respectively). This is in contrast with ourprevious finding that the Ig-positive bone marrow cell subset contained considerably higher frequency of IBL-2 cells, ranging between



the 60-70% of total (mature) B cells (Balogh et al., 1995) The B220- population could be resolved into two strikingly different subsets: one is IBL-2-neg- ative, whereas the other one was foundto reactwith this antibody very intensely (IBL-2hi). Slightly more than 50% of the latter cells also expressed the L- selectin(bottom right panel) at adetectable level.As theB-cellprecursors expresstheB220antigenrather early in theirdevelopment, however, it is likely that the majority of B220- population is composed of non-B lineage cells.

Although the expression patterns ofL-selectin by

B220+/IBL-2 andB220+/IBL-2 populations donot differ from each other significantly (top middle and rightpanels), thereis analmost threefold increase of theMEL-14positivesubset within theB220+/IBL-2hi

compartment (bottom middle panel). The question may arise whether the L-selectin molecule is func- tional ontheseB220+/IBL-2lorB220+/IBL-2hicells.

It has been demonstrated that even though the

granulocytic cells may become MEL-14 positive uponthe in vitro culture of theirL-selectin negative precursors induced by a variety of soluble factors, theyareunabletobindtoHEVcells,presumablydue to the lack of other adhesion molecules (Salmi and Jalkanen, 1992).

Toourknowledge,thereare nodataconcerningthe L-selectin expression during the various stages of murine B-cell differentiation in the bone marrow.

Therefore,wecanonly extrapolatefrom data obtained inhumans, indicating that the expression of CD62Lis restricted to the the later phase ofmedullary B-cell differentiation (Kansas and Dailey, 1989).

IBL-2 Phenotype of PeripheralB Cells in SCID Transplantedwith NormalSpleen Cells

Our previous findingindicatedthelocation-dependent reactivity of the IBL-2 mAb onB cells from various peripheral lymphoid organsofnormallymphopoietic


R3 FI4


c ,/ ,


10 101 1; 10 1,







Region 6

),0, 1;2




FIGURE Relationship between the expression ofL-selectinand IBL-2 antigenonB-cell precursorsinthebonemarrow. Adult bone marrowcellsdepletedof IgM-positive cellswere stained with anti-B220and IBL-2 and MEL-14 mAbs labeledwith different fluorochromes asdescribed in Materialsand Methods. Thevariousregions(3-6)shownonthecontourplot (gatedonlymphocytes)wereusedtoanalyze the expression ofL-selectinby the differentsubsets (histograms). The numbers atthe regions indicatethe percentageofpositive cells obtainedbyanirrelevantcontrolratIgG.





mice. In oursubsequentstudies, weused SCID mice as recipientsto studythe possiblephenotypic altera- tionsaffecting the IBL-2 antigen expression ofBcells upon their migration from the spleen to the lymph nodes. BALB/c-derived splenic cells as IBL-2-posi- tive cell source was employed. Three days after the intravenous administration oflymphocytes, different lymphoid organs of the recipients were assayed for theIBL-2 profile ofBcells(identifiedasIgM-positive cells). Wefoundthis timepointastheearliest toallow lymphocytes to be obtainedfrom lymph nodes (LN) in sufficent amountforflowcytometry.

By the end of this period, the overwhelming majorityofBcellsrecovered from the recipientsLNs had become IBL-2-negative,eventhoughthe original spleen-cell suspensioncontained asignificantamount of IBL-2l B cells. On the other hand, a significant proportionofBcells of the hostsspleens still retained the IBL-2 antigen on their surface. It is noteworthy that, compared to BALB/c control spleens, the IBL- 2-negative B-cell subset slightly increased, and the size of the IBL-2hi compartment was also reduced (Table I). The reasons for these discrepancies are unclear. Ourhypothesisisthatitprobablyreflects the difference in the lymphopoietic homeostasis of the spleen between the normal mice and Spl-SCID. In normal mice, the splenic influx of B cells is maintained from both the de novo formed B cells released from the bone marrow that are relatively immature (Allman et al., 1993) and fully mature B cells returning from other peripheral lymphoid organs. In Spl-SCID mice, the former source is negligible, whereasa considerable portion ofB cells inoculatedmayhaverecirculatedseveraltimesduring the 3-day period, taking into account the relatively

fastspeed of splenic homing (Brelinskaet al., 1984;

Willfuhr et al., 1989). The T cell remained IBL- 2-negative.

Thedual staining ofsplenocyteswith an anti-CD45 and IBL-2 mAbs revealed three main populations:



CD45+/IBL-21, and CD451/IBL-2hi.

A small, butconsistentlydetectable subsetexpressed the CD45+/IBL-2hiphenotype (not shown). Ofthese, the CD45/IBL-2hisubsetmay represent some extra- medullary erythroid-committed progenitors (manu- script in preparation). The origin of IBL-22hi non-B cells (donor/recipient)inthetransplantedanimals was notfurther investigated.

Thecontrol SCID mice did not contain detectable number ofB cells, eventhough someThy-l-positive cells could be observed. Another findingwasthatthey also almost completely lack the IBL-2l population, whereas the IBL-2hisubsetisclearlypresent,approxi- mately at the same frequency as in normal BALB/c mice (not shown).

The tissue distribution of the IBL-2-reactive ele- mentsinthespleenappearedtobesimilar inboth the transplanted and control SCID mice (Figure 2). The stronglypositive cells tendto formaring around the white pulp, where the cells are arranged in tight clusters containing around 20 to 70 cells. The similarity of immunohistochemical staining of the spleen of the control and injected SCID mice with IBL-2 mAbtogetherwithFACSdataindicatethat the majority of these bright cells are of non-B lineage.

However, attheinterpretationof the negativeimmu- nohistochemical staining of a B-cell area, one must take into account that, according to our quantitative FACS data, the level of IBL-2 antigen expressionon

TABLE DistributionofIBL-2-ReactiveBCellsinSCIDMice

Cellsample analyzed IBL-2-negative IBL-2 IBL-2

BALB/cspleen 34.7 4.2 47.1 3.2 17.9+_3.7

BALB/clymphnode 94.4 3.4 2.7_+0.7 2.1 0.6

Spl-SCID spleen 57.3 4.2 38.3 4.7 4.7 1.3

Spl-SCID lymphnode 91.7 6.4 3.4 1.4 1.9 0.8

Note:Theresults ofspleenarethe average SDoffive miceanalyzedindividually; thelymphnode resultsarethe average SD ofpooled lymphnode suspensions from fourmice.TheB cellswereidentifiedusing biotinylated anti-IgMantibodies.



supernatant. After 1-hrincubation at room tempera- ture, the specimens were washed and further incu- bated in the dark with FITC-conjugated affinity- purifiedsheep anti-ratIgGantibodies. After washing, the specimens were mounted with PBS-glycerol and viewed under a Nikon FXA epifluorescent micro- scope.

fixed in 1%bufferedparaformaldehyde. Thesamples were run on a Becton-Dickinson FACSCalibur flow cytometer and analyzedwith the CellQuest software package.


Depletion ofB Cells from theBone Marrow

The bone marrow cells were depleted of mature B cells by using rosette technique. Briefly, the bone marrowcellswere incubated with rat anti-mouseIgM mAb (Serotec, UK) followed by washing. The cells were further incubated with sheep erythrocytes (SRBC) precoatedwith affinity-purifiedsheepanti-rat

IgG.The mixture wasincubated at4C,with constant rotation in PBS contatinig 0.1% BSA and Na-azide.

The rosetted cells were rerosetted by adding SRBC precoatedwith rat IgG(Hunt, 1986).

Flow CytometricAnalyses

Theflow cytometricanalyses wereperformedoncell suspensions fromvariouslymphocytesourcesusinga cocktail of monoclon’al antibodies. For two-color staining, the cells were incubated withIBL-2 super- natant, followed by FITC-conjugated anti-rat IgG.

Theresidualbindingsitesof thesecondaryantibodies were blocked by normal rat serum. After washing, biotinylatedratmAbs (anti-mouse Thy-1, anti-mouse

IgM [LO-MM-9, Serotec] anti-mouse CD45) were added, that were subsequently detected with PE- streptavidin (Sigma).

The expression of IBL-2 antigen correlated with that ofL-selectin onBcells andontheirprecursorsin the bone marrow was detected using a three-color staining procedure. Normal bone marrow or spleen cells were incubated with PE-labeled anti-mouse CD45RA mAb as a lineage marker and biotinylated IBL-2 mAb, which was revealed using CyChrome- streptavidin (PharMingen, USA). The appearance of L-selectin on the B220-positive compartment was determined by their subsequent staining with FITC- labeled MEL-14 mAb. After staining, the cells were

The authors wish to thank Dr. Katalin Pfil6czi (NationalInstituteforHaematologyandImmunology, Budapest) forher generosityinproviding access to a flow cytometer. This workwas supported by OTKA Grants No. F016695 (P.B.) and T 16978 (I.J.)


AllmanD.M.,FergusonS.E., LentzV.M.,andCancroM.P. (1993).

PeripheralBcellmaturationII.Heat-stable antigenhisplenicB cellsare animmunedevelopmentalintermediate intheproduc- tion of long-lived marrow-derived B cell. J. Immunol. 151:


Balogh P., Beb6kZs, and N6meth P. (1992). Cellularenzyme- linked immunocircle assay. A rapid assay of hybridomas produced against cell surface antigens.J.Immunol. Meth. 153:


Balogh P.,SzekeresGy,and NdmethP. (1994). Hapten-mediated identification of cell membrane antigens using an anti-FITC monoclonal antibody.J.Immunol. Meth. 169: 35-40.

Balogh P., andKumnovicsA. (1995).Tissue-associatedpheno- typic heterogeneity of peripheralB cellsin mice.Immunology 86: 560-567.

Bradley L.M., Watson S.R.,andSwainS.L. (1994). Entryofnaive CD4Tcellsintoperipherallymphnodes requiresL-selectin.J.

Exp.Med. 180: 2401-2406.

Brelinska R., Pilgrim C., and Reisert I. (1984). Pathways of lymphocytemigrationwithinthe periarteriolar lymphoid sheath ofratspleen.Cell. TissueRes.236: 661-667.

Cyster J.G., and Goodnow C.C. (1995). Pertussis toxin inhibits migration ofBandT lymphocytesintosplenicwhitepulpcords.

J.Exp.Med. 182:581-586.

Hunt S.V. (1986). Preparative immunoselection of lymphocyte populations. InHandbook of ExperimentalImmunology, Weir D.M.,etal., Eds. Oxford: Blackwell),pp. 55.8-55.12.

Kansas G.S., and Dailey M.O. (1989). Expression of adhesion structuresduringBcelldevelopmentin man.J.Immunol. 142:


KraalG.,HoebenK., Breve J.,andvandenBergT.K. (1994).The role of sialic acid in the localization of lymphocytes in the spleen.Immunobiology 190: 138-149.

KraalG., Schornagel K.,StreeterP.R.,HolzmannB.,and Butcher E.C. (1995). Expression of the mucosal vascular addressin, MAdCAM-1,onsinus-lining cellsinthespleen. Am. J.Pathol.

147: 763-771.

LyonsA.B., andParishC.R. (1995). Aremurine marginal-zone macrophages the splenicwhitepulp analogof highendothelial venules?Eur.J. Immunol. 25: 3165-3172.



MasonD.W.,PenhaleW.J.,and SedgwickJ.D. (1987).Preparation oflymphocyte subpopulations. In Lymphocytes: A practical approach,KlausG. G. B.Ed.,(Oxford: IRL Press),p. 35.

Pabst R., andWestermann J. (1991). The role of the spleen in lymphocyte migration.ScanningMicrosc.5: 1075-1079.

Papayannopoulou T.,CraddockC.,NakamotoB., Priestley G.V., and WolfN.S. (1995).TheVLA4/VCAM-1 adhesionpathway defines contrasting mechanisms oflodgement oftransplanted murine hemopoietic progenitors between bone marrow and spleen. Proc.Natl. Acad.Sci.USA92: 9647-9651.

Parish C.R., and SnowdenJ.M. (1985). Lymphocytes express a diversearray of specific receptors for sulfated polysaccharides.

Cell.Immunol.91: 201-214.

PickerL.J.,and ButcherE.C. (1992). Physiologicalandmolecular mechanismsoflymphocytehoming. Annu. Rev.Immunol. 10:


Salmi M., and Jalkanen S. (1992). Regulation of L-selectin expression on cultured bone marrow leukocytes and their precursors. Eur. J.Immunol.22: 835-843.

StevensS.K.,WeissmanI.L.,and ButcherE.C. (1982).Differences in the migration of B and T lymphocytes: Organ-selective localization invivoand the role oflymphocyte-endothelialcell recognition.J.Immunol.128:844-851.

Van Ewijk W., and Nieuwenhuis P. (1985). Compartments, domainsand migrationpathwaysof lymphoid cellsinthe splenic pulp.Experentia 41: 199-200.

Weston S.A.,and ParishC.R. (1992).Calcein:Anovelmarker for lymphocytes which enter lymph nodes. Cytometry 13:


Willfuhr K.U., Westermann J., and Pabst R. (1989). Absolute numbers oflymphocytesubsets migratingthroughthe compart- ments of the normal and transplanted rat spleen. Eur. J.


YoshidaK., MatsuuraN.,TamahashiN.,and TakahashiT. (1993).

Developmentof antigenic heterogeneity in the splenic mesh- work ofsevere combined immunodeficient(SCID) miceafter reconstitution withTandB lymphocytes.Cell.Tissue.Res.272:



Submit your manuscripts at http://www.hindawi.com

Stem Cells International

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014



Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Behavioural Neurology


International Journal of

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Disease Markers

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014


Research International


Journal of

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

PPAR Research

The Scientific World Journal

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Immunology Research

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Journal of


Journal of

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Computational and Mathematical Methods in Medicine


Journal of

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Research and Treatment


Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporation

http://www.hindawi.com Volume 2014

Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014 Hindawi Publishing Corporation



Documents relatifs

Research from these diverse fields has consistently demonstrated that CD24 functions as a cell surface receptor, mediates the way cells adhere to neighbouring cells, and moderates

FIGURE 2 | Schematic depiction of process for isolation antigen-specific B cells using adhesion to antigen-expressing cells, fluorescent antigen capture, upregulation of B

This is generally not a problem because from a K-star revealing grammar it is always possible to define a simple K-star grammar that is a generalization of the former grammar:

In terms of limitations it should be noted that the generalizability is restricted due to the relatively small number of informants. Also, sleep deprivation and hal-

Domaines d’utilisation 135 de portée, ceux de ce carnet sont plus diversifiés mais aussi plus singuliers : on y trouve un abaque pour le calcul de la distance mesurée et de l’angle

Un enfant demande à son père : “Dis papa c’est maman ou toi qui m’a donné mon intelligence ?” Le père répond : “C’est sûrement ta mère parce que moi je

2) A l’aide d’un algorithme, donner, au jour près, le temps nécessaire pour que le plant de maïs atteigne une hauteur supérieure à 1, 5 m.. 3) On s’intéresse à la vitesse

Measuring a quantity is therefore a good way to prepare an ensemble of identical microsystems(!), as the subensemble corresponding to a particular eigenvalue is collectively


This figure depicts (1) the data acquisition, pre-processing, and normalization, as well as the mapping the cell population hierarchy; (2) the building of the methods by research

Normal erythropoiesis is simulated in two dimensions, and the influence on the output of the model of some parameters involved in cell fate (differentiation, self-renewal, and death

An alternative approach, based on a new Digital Image Correlation scheme (Q4-DIC (Besnard et al., 2006)) and on the Equilibrium Gap Method (EGM (Claire et al., 2002, 2004)),

An analysis of the amino acid sequence showed that the two cysteines essential for myomaker fuso- genic function were also present in the trout myomaker protein at positions 219

Control for Dynamic Positioning and Way- point Tracking of Underactuated Autonomous Underwater Vehicles Using Sliding Mode Control.. The MIT Faculty has made this article

L’accès à ce site Web et l’utilisation de son contenu sont assujettis aux conditions présentées dans le site LISEZ CES CONDITIONS ATTENTIVEMENT AVANT D’UTILISER CE SITE WEB.

clusters represent five different PEtn transferase families as follows; blue, lipid A-specific PEtn transferases, including EptA; green, PEtn transferases specific for the 6 position

Renunciation of health care by people living with HIV in France is still associated with discrimination in health-care services and social insecurity - results from the

of DNA and RNA results in the Términos Lagoon showed similar trends, with total and active communities presenting a strong zonation between the eastern, middle, and western parts of

Using this debugging process and several other real ontologies debugging one, we found out that in several occasions domain experts were just changing axioms from the original

(b–e) IL-6 concentration in supernatants from a 1-day culture of total BM cells recovered from healthy and paraplegic mice (b), total BM cells from healthy mice mixed with the

Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. A Cre-inducible diphtheria