IMMUNOLOGY AT MOUNT SINAI

Mononuclear phagocyte diversity in the intestine

Milena Bogunovic • Arthur Mortha •

Paul Andrew Muller • Miriam Merad

� Springer Science+Business Media, LLC 2012

Abstract Present in all organs, mononuclear phagocytes consist of a heteroge-

neous population of hematopoietic cells whose main role is to ensure tissue

homeostasis through their ability to scavenge cell debris, promote tissue repair and

maintain tolerance to self-antigens while simultaneously inducing innate and

adaptive immune responses against foreign antigens that breach the tissue. The

intestinal mucosa is particularly exposed to foreign antigen, through constant

exposure to high loads of commensal bacteria and dietary antigens as well as

providing a site of entry for viral and bacterial pathogens. The molecular mecha-

nisms that control the intestinal ability to distinguish between ‘‘innocuous’’ and

‘‘dangerous’’ antigens remains poorly understood although it is clear that mono-

nuclear phagocytes play a key role in this process. This review highlights recent

advances in our understanding of heterogeneous origin of the mononuclear

phagocytes that inhabit the intestinal mucosa and discusses how developmental

diversity allows for functional diversity to ensure intestinal integrity.

Keywords Mononuclear phagocytes (MPs) � Dendritic cells (DCs) �Macrophages � Intestine �Mucosa � Lamina propria �Muscularis

Introduction

Mononuclear phagocytes (MPs) represent a small popula-

tion of hematopoietic cells that populate most tissues and

share the ability to sample the extracellular milieu. In the

intestine, MPs are strategically located below the mucosal

epithelium allowing them to be in close contact with

luminal contents. They are also distributed throughout the

submucosa and the muscularis layer, which faces the

peritoneum. Tissue MPs consist of two main cell popula-

tions that include dendritic cells (DCs) and macrophages.

The central role of macrophages is to sustain tissue

homeostasis and repair, whereas the major function of DCs

is to capture and process antigenic material in the form of

peptide/major histocompatibility complex (MHC) com-

plexes that can be recognized by T lymphocytes. Upon

antigen uptake and maturation, DCs migrate from the

intestinal mucosa to the T cell areas of the mesenteric

lymph nodes (LNs) and promote the induction of adaptive

effector responses against pathogens that breach the

intestine or maintain T regulatory responses to commensals

M. Bogunovic (&) � A. Mortha � P. A. Muller � M. Merad (&)

The Immunology Institute, Mount Sinai School of Medicine,

One Gustave L. Levy Place, New York, NY 10029, USA

e-mail: milena.bogunovic@mssm.edu

M. Merad

e-mail: miriam.merad@mssm.edu

M. Bogunovic � A. Mortha � P. A. Muller � M. Merad

Department of Oncological Sciences, Mount Sinai School

of Medicine, One Gustave L. Levy Place, New York,

NY 10029, USA

Milena BogunovicMiriam Merad

123

Immunol Res

DOI 10.1007/s12026-012-8323-5

or self-antigens. This review summarizes recent advances

in our understanding of the diversity of the MP system

within the gut in the context of its developmental properties

and its role in gut immunity.

Architecture of the intestinal mononuclear phagocyte

system

Mucosal DCs

The intestinal mucosa consists of simple columnar epi-

thelium that provides an interface with the antigen-rich

luminal environment, the lamina propria and its lymphoid

structures also called gut-associated lymphoid tissue

(GALT) that include small lymphoid follicles scattered

throughout the intestinal mucosa as well as large organized

lymphoid structures called Peyer’s patches, and the mus-

cularis mucosae [1]. Similar to all DCs, mucosal DCs are

positive for the hematopoietic marker CD45 but lack

lymphocyte- and granulocyte-specific markers, and con-

stitutively express high MHC class II (MHCII) levels and

the integrin CD11c [2]. Mucosal DCs are distributed

throughout the intestinal tissue, forming an organized cel-

lular network in the lamina propria facing the lumen [3],

and are present in the GALT [4]. The phenotype of DCs in

PPs and mesenteric LNs that drain intestinal tissues have

been largely studied [5, 6], but the diversity of mucosal

DCs that accumulate in non-lymphoid tissues is only

starting to be unraveled.

Non-lymphoid tissue mucosal DCs accumulate mainly

in the lamina propria although some DCs can be found in

the epithelium. MHCIIhiCD11chi DCs can be further divi-

ded into two main populations best characterized as

CD103?CD11b?CX3CR1 (CX3C-chemokine receptor 1)-

and CD103-CD11b?CX3CR1? subsets. In addition, a

minor (5–10 % of MHCIIhiCD11chi cells) CD103?

CD11b-CD8a?CX3CR1- DC population found in muco-

sal cell suspensions is thought to reside in the isolated

lymphoid follicles scattered throughout the intestinal

mucosa and is a part of the GALT (Fig. 1, 2; Table 1)

[7–9]. DC subset distribution in the gut varies anatomi-

cally, with CD103?CD11b? DCs present at highest num-

bers in the duodenum and CD103-CD11b? DCs enriched

in the large bowel [10]. Recent studies further divide

CD103-CX3CR1? DC into CX3CR1hi and CX3CR1lo

subsets [11, 12], although it is not clear at this point

whether these cells are developmentally or functionally

distinct.

Although several phenotypically distinct DCs have been

described in the literature, we will discuss only DC subsets

with distinct phenotype, origin and function. This review

does not include plasmocytoid dendritic cells (pDCs), also

known as type I interferon-producing cells (IPCs). Though

these myeloid cells share a developmental pathway with

conventional DCs [13] and are abundant in the gut [14],

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CD11c hi

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LP MPGated on CD45+MHCIIhi

Muscularis MP

CD103+CD11b+ LP DC

CD103_CD11b+ LP DC

CX3CR10 10 2 103 104 105

B

A

Fig. 1 Anatomical distribution of the intestinal mononuclear phago-

cyte (MP) subsets in the intestine. a Flow cytometry dot plots show

the phenotype and percentages of intestinal MPs in single cell

suspensions obtained from different anatomical compartments of the

small bowel (SB). The lamina propria (LP) and muscularis layers (leftpanel) were separated and single cell suspensions were analyzed by

seven-color flow cytometry. The results were compared to the whole

SB cell suspension devoid of Peyer’s patches (right panel). To define

CD11chi and CD11clo DCs, gates were set on viable

DAPI-CD45?MHCIIhi cells. CD11chi MPs were further divided into

CD103?CD11b-, CD103?CD11b? and CD103-CD11b? DCs.

CD11clo MPs form a homogenous population. b Flow cytometry

histograms represent the levels of CX3C-chemokine receptor 1

(CX3CR1) expression by lamina propria CD11chi CD103?CD11b?

and CD103-CD11b? DC subsets in transgenic CX3CR1-GFP

reporter (CX3CR1?/GFP) mice

Immunology Institute at the Mount Sinai School of Medicine

123

they are poor phagocytes [15] and are not considered to be

a part of the MP system.

Mucosal macrophages

The phenotype of intestinal macrophages is controversial.

Macrophages are classically defined as CD45?MHCIIlo

CD11cloF4/80hiCD11bhi cells. However, in the intestine,

the vast majority of CD45?MHCIIloCD11cloF4/80hi

CD11bhi cells appear to lack CX3CR1, express eosinophil-

specific marker SIGLEC-F and have eosinophil-like

morphology (Fig. 3) (M. Bogunovic and M. Merad,

unpublished observation). Recent studies suggest that

CD45?MHCII?CD11chiCD103-CD11b?CX3CR1? lamina

propria DCs, which also express F4/80 [8], are in fact

macrophages (discussed in [16]) based on their distinct cel-

lular morphology consisting of a large vacuolar cytoplasm,

selective expression of phagocytosis-associated genes and

enhanced phagocytic activity in vitro [8, 12, 17–19].

Muscularis MPs

Intestinal muscularis externa, comprised of longitudinal

and circular layers of smooth muscles, is positioned under

the mucosa and submucosa away from the antigen-rich

luminal environment and maintains continued peristalsis to

allow passage of digested material along the gut. A net-

work of MHCII? phagocytes exists in the intestinal mus-

cularis and was originally described as macrophages [20]

but later classified as DCs [21]. We have shown that the

intestinal muscularis contains a homogeneous population

of MHCIIhiCD11cloCD103-CD11b? cells that also express

CX3CR1 and F4/80 [8]. In a whole intestinal cell suspen-

sion, muscularis MPs can be distinguished from CD11chi

Fig. 2 Anatomical distribution of intestinal DC subsets in the steady

state. CD11chiCD103?CD11b? dendritic cells (DCs) (blue) and

CD103-CD11b? DCs (black) are distributed throughout the lamina

propria whereas CD11chiCD103?CD11b- DCs (red) are localized in

the isolated lymphoid follicles. CD103?CD11b? DCs migrate to the

mesenteric lymph nodes in a CCR7-dependent fashion. The intestinal

muscularis externa is a separated layer of the smooth muscle tissue

that harbors a unique population of CD11cloCD103-CD11b?

phagocytes

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123

Table 1 Developmental and functional properties of intestinal lamina propria DC subsets

Lamina propria

MP subsets

CD103? CD11b- CD103? CD11b? CD103- CD11b?

Surface marker

expression

MHCll? CD11chiCD103? CD11b-

CD8a? CX3CR1- F4/80-

CD172alo*CD64-*

MHCII? CD11chi CD103? CD11b?

CD8a- CX3CR1- F4/80lo CD172aint*

CD64-*

MHCll? CD11Chi CD103- CD11b?

CD8a- CX3CR1? F4/80?

CD172ahi* CD64?*

DC subset

deficient mice

Flt3-/-**, Batf3-/-, ld2-/-, irf8-/- Flt32/2, Csf2r2/2**, Notch2CD11c Csf1r2/2**

Developmental

origin

CDP, pre-DC CDP, pre-DC Monocytes

Anatomical

location in the

steady state

GALT and MLN Lamina propria, enriched in small bowel Lamina propria, enriched in colon

Cytokines that

control

development

FLT3L FLT3L, GM-CSF M-CSF

Function ex vivo:

T cell response Th1 induction Treg and Thl, Th17 induction Treg expansion

Phagocytosis N.D. Less efficient More efficient

Cytokines IL-6, IL-12 IL-6, TGFb, RA, IL-23 IL-10, TNF, IL-6, IL-12, IL-23, IL-27

T cell indep. IgA

CSR

Not involved Involved N.D.

Function in vivo N.D. Migrate to MLN, oral tolerance,

antimicrobial defense

Oral tolerance, inflammatory cytokine

secretion, colitis

Mononuclear phagocytes (MP); CD172a is also known as SIRPa; CD64 is also known as Fcc receptor I (FccRI); basic leucin zipper tran-

scriptional factor ATF-like 3 (Batf3); inhibitor of DNA-binding protein-2 (Id2); interferon-regulatory factor 8 (Irf8); neurogenic locus notch

homolog protein 2 (Notch2); macrophage colony-stimulating factor (M-CSF), its receptor is encoded by colony-stimulating factor 1 receptor

gene (Csf1r); granulocyte macrophage colony-stimulating factor (GM-CSF), its receptor is encoded by colony-stimulating factor 2 receptor gene

(Csf2r); FMS-related tyrosine kinase 3 ligand (FLT3L), its receptor is encoded by FMS-related tyrosine kinase 3 gene (Flt3); common dendritic

cell precursor (CDP); dendritic cells (DC); Gut-associated lymphoid tissue (GALT), Mesenteric lymph node (MLN); CD4? T helper cells (Th);

CD4? T regulatory cells (Treg); immunoglobulin (Ig); interleukin (IL); tumor necrosis factor (TNF); retinoic acid (RA); class switch recom-

bination (CSR); not determined (N.D.)

* Milena Bogunovic, Jennifer Miller and Miriam Merad, unpublished

** Incomplete depletion

0 102 103 104 1050

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0 102 103 104 1050

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100

0 102 103 104 1050

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3000

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SS

C

SS

C

CX3CR1-GFP Gr-1

1(89%)

2 (10.1%)

1A

2

1B

1A

21B

A BGated on CD45+MHCII-

SIGLEC-F

Fig. 3 Non-DC myeloid cell in the intestinal mucosa. a Dot plots

show the phenotypes of CD45?CD11b?MHCIIlo/- cell populations in

the SB intestinal mucosa. SSChiCX3CR1-Gr1loSIGLEC-F? cells (1a)

represent eosinophils; SSCintCX3CR1-Gr1hiSIGLEC-F?/- cells (1b)

are likely neutrophils; SSCloCX3CR1?Gr1hiSIGLEC-F- cells (2) are

likely undifferentiated monocytes. b Cytospin of purified

CD11b?MHClo/- cells demonstrates that the majority of this

population are polymorphonuclear eosinophils

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123

lamina propia DCs by the low expression of CD11c (Fig. 1,

2) [8]. However, most studies that use whole intestinal

digests unsuitably refer to the muscularis CD11clo MP

population as lamina propria macrophages [12, 17–19, 22].

Regulation of intestinal mononuclear phagocyte

development

Origin of intestinal MPs

Commitment to the MP lineage occurs at the level of

macrophage and DC precursor (MDP), a dedicated mye-

loid-derived bone marrow (BM) precursor that has lost

granulocytic, erythrocytic and megakaryocytic potential

[23]. MDP maintains a dual potential, differentiating into

either monocytes, which are thought to give rise to most

tissue macrophages [24] or to a DC-restricted progenitor

called the common DC precursor (CDP) that gives rise to

both classical and plasmacytoid dendritic cells [13, 25, 26].

In the BM, CDP differentiates into either plasmacytoid

DCs or so-called pre-DCs [26]. Pre-DCs migrate through

the blood to lymphoid organs where they differentiate into

classical CD8? and CD8- DCs [26]. Pre-DCs can also

migrate to the non-lymphoid tissues to give rise to classical

DCs [27].

In the intestine, CDPs and pre-DCs give rise only to

CD103? DC populations (both CD103?CD11b- and

CD103?CD11b?) but not to CD103-CD11b? DCs. In

contrast, monocytes differentiate into CD103-CD11b? but

not CD103? DCs [8, 28], indicating that intestinal CD103?

and CD103- DCs derive from two independent lineages

(Fig. 4). In addition, the distinct monocyte origin of

CD103-CD11b? DCs is in agreement with the fact that

these cells may indeed represent intestinal macrophages.

Regulation of MP homeostasis in the intestine

FMS-like tyrosine kinase 3 ligand (FLT3L) and its receptor

FLT3, granulocyte macrophage colony-stimulating factor

(GM-CSF) and its receptor GM-CSFR and macrophage

colony-stimulating factor (M-CSF) and its receptor

M-CSFR are key molecules involved in MP development

and homeostasis [29]. Flt3L controls the commitment and

differentiation of the DC lineage, and GM-CSF is essential

for the differentiation of DCs in vitro and is thought to

control the development of inflammatory DCs in vivo,

whereas M-CSF controls macrophage development and

homeostasis [30].

Recent studies established that these cytokines and their

receptors control intestinal MP development differently.

Flt3L and Flt3 control the differentiation of

CD103?CD11b- and CD103?CD11b? DCs [11, 28].

GM-CSF and GM-CSFR control the differentiation of

CD103?CD11b? DCs [8, 11], while M-CSFR controls

CD103-CD11b? lamina propria DC homeostasis (Fig. 4) [8].

Several transcription factors have recently been shown

to control DC development in vivo. Interferon-regulatory

factor (IRF) 8 belongs to the family of IRF proteins. Early

studies on the role of IRFs in DC development demon-

strated that in vitro development of BM-derived DCs

supplemented with Flt3L is preferentially controlled by

Irf8, while DCs generated in the presence of GM-CSF rely

on Irf4 [31]. The inhibitor of DNA-binding protein-2 (Id2)

controls formation of peripheral lymphoid organs including

GALT as well as the development of natural killer (NK)

cells, lymphoid tissue inducer (LTi) cells, natural helper 2

(NH2) cells [32–34] and epidermal Langerhans cells [35].

Recently, the transcription factor Batf3 (also known as Jun

dimerization protein p21SNFT) was shown to be highly

expressed in classical DCs [36]. Irf8, Id2 and Batf3 are

selectively required for the development of lymphoid tissue

CD8a? DCs [35–37] and lung and skin CD103? DCs [2,

27, 38]. Analysis of intestinal MPs in Id2, Irf8 or Batf3

deficient mice revealed a total absence of CD103?CD11b-

DCs, whereas CD103?CD11b? DCs remained intact in

these mice [8, 27, 39]. In contrast, the specific depletion of

Notch2 in CD11c? cells (Itgax(CD11c)-cre x Notch2flox/flox

mice) results in the selective depletion of CD103?CD11b?

lamina propria DCs but not CD103?CD11b- DCs [40].

Id2, IRF8, Batf3 and Notch2 do not play a role in the

development of CD103-CD11b? DCs.

Intestinal microbiota and mucosal MP development

Little is known about the influence of the intestinal mic-

robiota on MP diversity in the intestinal mucosa. A recent

study revealed that the total numbers of intestinal CD11c?

DCs are reduced in germ-free mice compared with specific

pathogen-free (SPF) animals [41]. Furthermore, this study

demonstrated that only CX3CR1? DC subset was signifi-

cantly reduced, whereas CD103? DCs developed normally

in the small and large bowel of germ-free animals, sug-

gesting the contribution of luminal microbiota to the

development of CX3CR1? but not CD103? DCs [41].

Diet and mucosal MP development

Retinoic acid (RA), a metabolite of the dietary component

vitamin A, plays a key role in the regulation of mucosal

immune responses [42]. Interestingly, mice deprived of the

dietary vitamin A accumulate high numbers of langerin?

DCs in the intestinal mucosa, GALT and mesenteric LNs

that control the induction of oral tolerance in these animals

[43]. DCs expressing the c-type lectin langerin accumulate

mostly in the skin and lung [44, 45] and are absent in the

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123

normal intestinal mucosa. These results indicate that die-

tary component likely influences DC differentiation and

function in the steady state.

Function of lamina propria mononuclear phagocytes

Sampling of luminal antigens

The epithelial cell monolayer covering the mucosal sur-

faces of the gut was originally thought to represent a

sealed barrier against non-invasive microbiota populating

the lumen. However, it now appears that subepithelial

DCs closely interact with the intestinal epithelium. They

can penetrate epithelial monolayers by projecting dendrite

extensions into the lumen allowing them to sample

luminal bacteria [3, 46]. In the terminal ileum, the process

of transepithelial dendrite formation and sampling is

dependent on CX3CR1, also known as fractalkine receptor

[3]. DC transepithelial protrusions were shown to be

dependent on the microbiota [41] but independent of

MyD88 [47]. CX3CR1 also controls the development of

the CD103-CD11b?CX3CR1? population likely through

the recruitment of its progenitors into the gut tissue, as

mice that lack CX3CR1 and its ligand CX3CL1 (also

known as fractalkine) have reduced numbers of the

intestinal CD103-CD11b?CX3CR1? DC subset [19].

Although the formation of transepithelial dendrites is

thought to be mainly restricted to the lamina propria

CD103-CD11b? DC subsets as it is the only DC subset

Fig. 4 DC-poiesis and cytokines regulating intestinal DC subsets.

Intestinal CD103?CD11b- DCs (red), CD103?CD11b? DCs (blue)

and CD103-CD11b? DCs (black) derive from bone marrow (BM)

progenitors. The granulocyte macrophage precursor (GMP) resides in

the BM and differentiates into the macrophages dendritic cell

precursor (MDP) that gives rise to monocytes or subsequently loses

macrophage potential by differentiating into the common dendritic

cell precursor (CDP). CDP develops into pre-DCs that exit the BM

and migrate into the tissue where they differentiate into FLT3-

dependent CD103? DCs (red and blue). CD103-CD11b? DCs

(black) arise from monocytes that leave the BM and circulate in the

blood. Once recruited into the tissue, circulating monocytes develop

into M-CSFR-dependent CD103-CD11b? DCs

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123

expressing CX3CR1 in the gut, subsequent studies have

suggested that chemokines other than CX3CL1 (such as

CCL20) and DC populations other than CX3CR1? DCs

can also contribute to transepithelial dendrite formation

[48]. Consistently, we have found that in contrast to

CD103-CX3CR1? DCs, which accumulate in the subep-

ithelial mucosal compartment, a significant number of

CD103? DCs are present in the epithelial layer [8], sig-

nifying that they too could potentially sample the luminal

antigens. Whether CD103? DCs sample through the for-

mation of transepithelial dendrites or other mechanisms

remains to be examined.

DC migration and antigen transport to the lymph nodes

The initiation of efficient adaptive immune response occurs

in the organized lymphoid structures [49]. Upon antigen

uptake and maturation, tissue DCs migrate to the afferent

lymphatics to present tissue antigens in the form of pep-

tide–MHC complexes to T lymphocytes [49]. Tissue DC

migration to the draining LNs in the steady state is thought

to control the induction of tolerance to self-antigens [50],

whereas DC migration during infection controls the

induction of effector immune responses against microbial

stimuli. Recent results revealed that lamina propria DC

Fig. 5 Functional implications of intestinal lamina propria DC

subsets in mucosal immunity. The cartoon demonstrates possible

scenarios that either lead to the maintenance of a tolerogenic state

(left panel), or the promotion of inflammation (right panel). In a

tolerogenic state (left), CD103?CD11b? DCs (blue) constantly

uptake bacterial and dietary antigens from the intestinal lumen and

transport them to the mesenteric lymph nodes (MLN). In the MLN

CD103?CD11b? DCs prime naı̈ve T cells to differentiate into

inducible T regulatory cells (iTregs). iTregs upregulate gut-homing

molecules CCR9 and a4b7 and home back to the lamina propria. In

the lamina propria, Treg expansion is controlled by IL-10 secreted by

CD103-CD11b? DCs to promote oral tolerance. Invasion of

pathogens in the mucosa results in inflammation followed by the

activation of both CD103?CD11b? DCs and CD103-CD11b? DCs.

CD103-CD11b? DCs adapt a pro-inflammatory phenotype and start

producing cytokines such as TNF, IL-12, IL-23 and IL-6.

CD103-CD11b? DCs might upregulate their migration to the MLN

and prime native T cells toward a Th17 phenotype. Furthermore

CD103?CD11b? DCs start to produce IL-23 which regulates the

expression of Th17- and innate lymphoid cell (ILC)-associated IL-22.

IL-22 regulates the production by epithelial cells of the antimicrobial

peptide RegIIIc Additionally, CD103?CD11b? DCs migrate to the

MLN and induce the differentiation of Th17 or Th1 phenotype that

promote local inflammation

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123

subsets differ in their ability to migrate to the mesenteric

LNs that drain the gut. CD103? DCs constitutively migrate

to the mesenteric LNs in the steady state and are the first to

migrate to the mesenteric LNs in the inflamed state, while

CD103- DCs migrate poorly to the mesenteric LNs in the

steady state [8, 11]. Upon inflammation CD103-CD11b?

DCs likely can reach the draining LNs with a delayed

kinetics (M. Bogunovic and M. Merad, unpublished

observation).

In the gut, DCs were shown to transport intestinal com-

mensals and pathogenic bacteria to the MLNs [51] through

TLR5-dependent mechanisms [52]. These results together

with the earlier data on luminal sampling of commensal

bacteria and Salmonella by CX3CR1? DCs [3, 46] empha-

size the importance of CX3CR1? DCs in gut immunity.

Tissue DC migration to the draining LNs is controlled by

the chemokine receptor CCR7 [53, 54]. CD103?CD11b?

DCs express much higher CCR7 levels in the steady state

compared with the CD103-CX3CR1? subset [8]. CCR7-

deficient mice have a strong reduction of the CD103?CD11b?

DC population in the MLNs [8, 55] and are compromised in

their ability to induce oral tolerance to ovalbumin, suggesting

that CD103?CD11b? DCs participate in the transport of

dietary antigens to the mesenteric LNs [56]. These finding are

consistent with earlier studies in rats showing that mucosal

CD103? DCs transport apoptotic epithelial cells to the mes-

enteric LNs [57]. These results are also supported by a more

recent report showing that CD103?CX3CR1- DCs are a

dominant DC population in the gut afferent lymphatic vessels

[11].

T cell priming

Differences in the ability of lamina propria DC subsets to

access the mesenteric LNs likely represent their distinct

contribution to mucosal immune responses. Consistent with

their constitutive ability to migrate to the mesenteric LNs,

CD103? DCs isolated from the lamina propria or mesenteric

LNs have a superior ability to induce the expression of

gut-homing molecules CCR9 and a4b7 integrin on T lym-

phocytes [55] and to drive the generation of Foxp3? T

regulatory (Treg) cells ex vivo compared with the CD103-

DC population. Ability of CD103? DCs to generate Foxp3?

Tregs ex vivo is dependent on TGF-b and RA [58, 59]

and, accordingly, CD103? DCs exhibit higher aldehyde

dehydrogenase (Aldh) activity [10, 11, 58, 59].

Subsequent studies also performed ex vivo revealed that

CD103-CD11b?F4/80? lamina propria ‘‘macrophages’’

can drive the generation of Tregs in a TGF-b-, IL-10- and

RA-dependent manner [10, 60] with a higher efficiency than

CD103? DCs [10]. A more recent study on oral tolerance in

vivo reconciled these two findings and showed that while the

induction of Tregs occurs in the mesenteric LNs and is

therefore dependent on steady-state migratory DCs (likely

CD103?CD11b? DCs), CD103-CD11b?CX3CR1? DCs

(likely correspond to the CD103-CD11b?F4/80? cells in

Denning’s studies [19]) control the expansion of Tregs in the

lamina propria [61]. It is important to note that all the studies

implicating the role of CD103? DCs in the induction of

Foxp3? Tregs have been performed ex vivo, and the exact

contribution of intestinal CD103? DCs to the induction of

Tregs in vivo remains to be established. Ex vivo studies also

revealed that lamina propria DCs can drive IL-17 and INF-cproduction by CD4? T cells in a TLR5-dependent manner

[62]. Th17 polarization was regulated by IL-6 selectively

produced by CD103?CD11b? DCs [10]. Consistently, the

specific loss of CD103?CD11b? DC population observed in

the mucosa of Itgax(CD11c)-cre x Notch2flox/flox mice lead to

the reduction of Th17 T cells, providing the first character-

ization of the DC subset driving Th17 formation in vivo in

the steady state [40].

Notably, recent studies also demonstrated that

CD103?CD11b-CD8a? DCs uniquely express TLR3 and

TLR7, lack regulatory properties along with retinoic acid-

converting enzyme Raldh2 expression and constitutively

produce IL-6 and IL-12p40. CD103?CD11b-CD8a? DCs

are potent inducers of Th1 but not Th17 response and are

less efficient in inducing cytotoxic CD8 responses com-

pared with CD103?CD11b?CD8a- DCs [63].

Immunoglobulin response

The intestinal mucosa is an important site of immuno-

globulin (Ig) A production, forming an extra layer of pro-

tection against commensal and pathogenic bacteria [64].

GALT DCs were originally thought to play a key role in B

cell homing and IgA class-switching through both T cell-

independent and T cell-dependent mechanisms [65, 66].

The so-called naturally occurring TNF/iNOS-producing

(TIP) DCs, named after the inflammatory monocyte-

derived TIP DCs described in the inflamed spleen [67],

were shown to control T cell-dependent IgA class-switch-

ing through the expression of TGF-b receptor and T cell-

independent IgA class-switching through production of

APRIL and BAFF [68]. Both processes require DC-

restricted iNOS production induced by bacterial commen-

sals through TLR stimulation [68]. Similar properties were

also described for CD11c?CD11b? lamina propria DCs

and were shown to depend on TLR5 [62]. Interestingly,

Id2-deficient mice that lack Peyer’s patches [33] and

CD103?CD11b- DCs [8, 27] retain intestinal IgA pro-

duction [62]. Consistently, CD103?CD11b-CD8a? DCs

enriched in Peyer’s patches [8] are effective inducers of

systemic IgG but are not involved in the regulation of

mucosal IgA synthesis [63].

Immunology Institute at the Mount Sinai School of Medicine

123

Control of intestinal homeostasis

Intestinal homeostasis depends on the delicate equilibrium

between inflammatory and anti-inflammatory factors. Each

intestinal DC population plays a unique role in regulating this

dynamic process. The lamina propria CD103-CD11b?

population provides a constitutive source of the regula-

tory cytokine IL-10 [10, 60]. IL-10 production by

CD103-CD11b? DCs is controlled by CX3CR1, and the

reduced levels of IL-10 in CX3CR1-deficient mice correlate

with impaired mucosal Treg expansion and inability to mount

oral tolerance [61]. Consistently, in a T cell transfer model of

colitis, IL-10 deficiency in myeloid cells prevents the sup-

pressive function of Tregs via the downregulation of Foxp3

[69]. The importance of the CD103-CD11b?CX3CR1?

population in maintaining intestinal integrity is further sup-

ported by two recent studies using naı̈ve T cell transfer and

DSS-induced colitis models [19, 41]. In both cases, CX3CR1

deficiency resulted in exacerbation of colitis. The strong

reduction of CD103-CD11b?CX3CR1? DCs/macrophages

in the lamina propria of CX3CR1-deficient mice is thought to

be responsible for the increased mucosal accumulation of

Th17 cells and disease aggravation [19].

CD103?CD11b? lamina propria DCs are also shown to

play an important role in intestinal homeostasis through the

enhancement of mucosal innate immune defenses. Sys-

temic administration of the TLR5 ligand flagellin leads to

IL-23 production, specifically by CD103?CD11b? DCs,

and IL-23 induced IL-22 upregulation by innate lymphoid

cells, followed by a rise in mucosal production of anti-

microbial peptide RegIIIc [70].

Several mouse models have demonstrated that develop-

mental or functional defects in the macrophage/DC com-

partment result in spontaneous inflammatory bowel disease

(IBD). For example, myeloid cell–specific depletion of

STAT3 in LysM-cre x Stat3flox/flox mice [71, 72], lack of

TLR5 [73] highly expressed by CD11b?CD11chi lamina

propria DCs [62], DC-specific loss of TGF-b activating

integrin avb8 in CD11c-cre x Itgb8flox/flox mice [74] and

constitutive ablation of DCs in CD11c-Cre/R-DTA mice that

express diphtheria toxin A chain (DTA) under the control of

CD11c promoter [75], all lead to spontaneous colitis. Addi-

tionally, deletion of Wnt-b-catenin signaling in intestinal

CD11c? cells (CD11c-cre x b-catflox/flox mice) exacerbated

DSS-induced colitis due to the reduced suppression and the

enhanced differentiation of Th1 and Th17 effector cells [76].

Induction of inflammatory response

DCs in inflamed tissue likely differ from those in the steady

state. Depending on the degree and phase of the inflam-

matory response, tissue DCs can be either reduced due to

their migration to the draining LNs or increased due to the

accumulation of newly recruited blood-derived cells.

Monocytes represent an important source of DCs in

inflamed tissue [67, 77], whereas the contribution of other

DC precursors to the DC pool in inflamed tissue is not yet

clear. In a T cell-dependent model of colitis, monocyte-

derived inflammatory CD103-CD11b?CX3CR1? DCs

express E-cadherin and produce pro-inflammatory cyto-

kines including IL-12p35, IL-12/23p40, IL-23p19, IL-6

and TNF [12, 78]. Reconstitution of DC-depleted mice

with monocyte-derived CD103-CD11b? DCs restores

mucosal inflammatory response after DSS treatment at

least in part via TNF production [28]. Consistently, exag-

gerated TNF production in TNFDARE mice results in severe

transmural intestinal inflammation [79–81]. Toxoplasma

infection also results in dramatic mucosal accumulation of

Gr1?F4/80? monocytes that express iNOS, TNF and IL-12

[82]. Interestingly, DCs isolated from the inflamed intes-

tinal mucosa of Toxoplasma gondii-infected mice express

p35 and p28 subunits of the IL-12 and IL-27 cytokines and

promote Treg conversion into CD4 effector cells [83].

These results suggest that monocyte-derived inflammatory

DCs could also contribute to intestinal inflammation

through their ability to revert Tregs into T effector cells.

Function of lamina propria DC subsets in mucosal

immune responses is summarized in Fig. 5 and Table 1.

Function of muscularis mononuclear phagocytes

Very little is known about the function of muscularis MPs.

They were originally described as phagocytic macrophage-

like cells [20]. More recently, muscularis MPs were shown

to express CD11c and induce antigen-specific CD4 and

CD8 T cell responses ex vivo, thus becoming classified as

DCs [21]. Interestingly, muscularis MPs are able to

respond to inflammatory changes in the intestinal mucosa

[21, 84, 85] by producing inflammatory chemokines [86]

and upregulating co-stimulatory molecules [21] likely to

provide a second line of defense against luminal threats.

They can also sense changes in the peritoneal environment

even in the absence of a pathogen and are implicated in the

development of postoperative ileus (POI) [87], an inflam-

matory condition of the gastrointestinal tract that results in

intestinal paralysis. In surgically manipulated areas of the

gut, the release of inflammatory mediators by muscularis

MPs is thought to directly impair smooth muscle contrac-

tility [87, 88]. However, it remained unclear how local

inflammation release can lead to a generalized intestinal

paralysis. Recent data suggest that abdominal surgery

promotes muscularis MPs to release IL-12 and activate

memory Th1 cells, which in turn migrate to intact areas of

the gut and spread inflammation [89, 90].

Immunology Institute at the Mount Sinai School of Medicine

123

Mononuclear phagocyte system in the human intestinal

mucosa

Very little is known about the phenotype and function of

MPs at the mucosal interface of the human gut. One study

demonstrated the cross-species preservation of the pheno-

typic and functional properties of CD103? DCs isolated

from the human mesenteric LNs [7]. CD103? DCs were

readily detected in the mesenteric LNs draining the normal

small intestine and displayed a more mature phenotype

compared with their CD103- counterparts. When incubated

with allogeneic CFSE-labeled peripheral blood lympho-

cytes (PBL), CD103? DCs upregulated the expression of

CCR9 on responding CD8? T cells to levels significantly

higher than their CD103- counterparts. Similar to mice,

induction of gut-homing molecules on T cells by human

CD103? DCs was dependent on RA receptor signaling. A

similar analysis was performed on mesenteric LNs from IBD

patients (Crohn’s disease) that drained the inflamed intes-

tine, but no differences were observed compared with

CD103? DCs from the normal mesenteric LNs [7].

A population of CD13? cells with morphologic features

of macrophages has been identified in the human intestinal

mucosa [91]. These cells do not produce proinflammatory

cytokines in response to inflammatory and bacterial stimuli

despite the expression of TLRs [91, 92] but have phagocytic

and bactericidal activity [91]. It is not clear whether these

cells are related to the CD103- mucosal DC population.

Summary

The intestinal MP system protects the mucosal interface

from potential threats and is a critical component of

mucosal immune responses. It plays an essential role in

initiating and maintaining immunity, while preserving

intestinal homeostasis during the steady state and inflam-

mation. Recent advances in the field have characterized the

complexity of MP system; however, our understanding of

the functional complexity and the underlying molecular

control of this cellular system remain in its early stages.

Acknowledgments We would like to thank M. C. Berin for her helpful

comments. M.B. is supported by a career development award from the

Crohn’s and Colitis Foundation of America and a primary caregiver

technical assistance supplement from the National Institute of Allergy and

Infectious Diseases. A.M. is supported by a fellowship from the German

Research Foundation (DFG), MO 2380/1-1:1. M.M. is supported by the

National Institutes of Health grants HL086899, AI095611 and CA154947.

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