Edited by: Marcela A. Hermoso, Universidad de Chile, Chile
Reviewed by: Eduardo J. Villablanca, Karolinska Institutet (KI), Sweden; Fernando G. Chirdo, National University of La Plata, Argentina
This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology
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Dendritic cells (DCs) mediate tolerance to food antigens, limit reactivity to the gut microbiota and are required for optimal response to intestinal pathogens. Intestinal DCs are heterogeneous but collectively generate both regulatory and effector T cell responses. The balance of outcomes is determined by the activity of functionally distinct DC subsets and their modulation by environmental cues. DCs constantly sample luminal content to monitor for pathogens; the significance of the various pathways by which this occurs is incompletely understood. Intestinal DC have distinctive properties shaped by local host, dietary and microbial signals. These properties include the ability to produce all-trans retinoic acid (RA) and imprint gut tropism on T cells they activate. In the steady-state, subsets of intestinal DC are potent generators of inducible Treg, aided by their ability to activate TGFβ and produce RA. However, responses induced by steady-state intestinal DCs are not exclusively regulatory in nature; effector T cells with specificity for commensal bacterial can be found in the healthy mucosa and these can be locally controlled to prevent inflammation. The ability of intestinal DCs to enhance effector responses in infection or sustain inflammation in disease is likely to involve both modulation of the local DC population and recruitment of additional populations. Immune pathways in the pathogenesis of inflammatory bowel disease can be mapped to DCs and in inflamed intestinal tissue, DCs show increased expression of microbial recognition machinery, activation, and production of key immunological mediators. Intestinal DCs may be targeted for disease therapy or to improve vaccine responses.
Dendritic cells (DCs) are bone marrow-derived antigen presenting cells which comprise two major subsets: conventional (or classical) DCs (cDCs) and plasmacytoid DC (pDC). They are developmentally distinct from both tissue resident macrophages and monocyte-derived populations (
cDCs play critical roles in immune regulation in the intestine and are the focus of this review. The reader is referred to a recent review article (
Intestinal cDCs are found within organized lymphoid tissue, including Peyer's patches (PP) (
Additional cell surface markers are used in particular species to define intestinal cDC subsets further. In mice, cDC1 are CD103+CD11b–, whereas cDC2 comprise CD103–CD11b+ cells and a gut-specific CD103+CD11b+ population (
Summary of the origins and properties of intestinal DC. FLT3L-dependent development of cDC gives rise to two major subsets via CDP and committed pre-cDC in the BM. cDC1 are XCR1+ and depend on transcription factors including IRF8 and BATF3; cDC2 are SIRPα+ and depend on transcription factors that include IRF4. Population of the intestinal mucosa may be via an intermediate gut-committed α4β7+ precursor [sometimes termed pre-mucosal (μ) DC] stage (
LP DC populations are dependent on FLT3L for development and are derived from a committed pre-cDC progenitor (Figure
To protect against luminal pathogens and establish regulatory response to innocuous antigens, DCs continuously sample intestinal contents (
Lymphocytes activated in gut lymphoid tissue traffic to the intestinal mucosa because they express specific adhesion molecules and chemokine receptors. The integrin α4β7 binds MAdCAM-1 expressed by intestinal vascular endothelium and facilitates entry to both the colon and the SI. The chemokine receptor CCR9 is required for entry to the SI, where its ligand CCL25 is expressed (
In the steady-state, intestinal DCs can induce Treg. In the mouse SI, induction of gut tropic Treg directed against soluble antigens, by both CD103+CD11b+ and CD103+CD11b– DCs, occurs in the mesenteric LN (
T cell responses stimulated by DCs in the steady-state are not exclusively regulatory. Effector T cells are present in the lamina propria of healthy mice and humans; although some of these may reflect past pathogen encounter others are specific for the commensal microbiota (
The ability of intestinal cDC to generate RA and promote tolerance requires active Wnt/β-catenin signaling with the cDCs (
The balance of responses induced by DC can change in the context of infection to favor effector mechanisms. Signaling through p38 MAPK in CD103+ mouse DC regulates the balance of Treg and Th1 development from naïve T cells (
A change in the balance of T cell responses induced by intestinal cDC may result from direct modulation by danger signals, altered conditioning of the resident cDC population or recruitment of distinct pro-inflammatory DC (Figure
Enhanced generation of effector T cells in response in infection and inflammatory disease. A number of mechanisms act to shift the balance of response induced by intestinal DC to favor the generation of effector responses. These are important for pathogen clearance but if dysregulated may lead to inflammatory disease. Increased exposure to PAMPS and DAMPS, as the result of loss of barrier integrity or tissue penetration by pathogens may be sensed by LP DC populations leading to their activation
In most tissues, exposure to microbial products is sufficient to convert immature cDCs to mature cells which generate potent effector responses. However, exposure to PAMPs from the commensal microbiota is likely to be a common occurrence in the healthy intestine and therefore a second signal may also be required. Indeed, mouse CD103+ SI cDCs can induce Treg even in the presence of the high level of costimulatory molecule expression characteristic of mature cDC (
Intestinal cDCs reside in the mucosa for a few days (
Intestinal cDC function may also be influenced remotely during their development in the bone marrow. Intestinal inflammation alters hematopoiesis to influence the development of monocytes and subsequently the intestinal populations derived from them (
Alternative precursors may also be recruited into the tissue under inflammatory conditions to provide cells with the ability to generate effector responses. Monocytes can give rise to DC-like cells (monocyte-derived DC; moDC) under inflammatory conditions (
Effector cells generated by DCs could also be released from local control within the tissues where diverse antigen presenting cell (APC) populations exert a local influence (
Irrespective of the combination of mechanisms which allow effector responses to be enhanced to deal with infections, a key unanswered question remains how these responses are confined to the pathogen and do not normally extend to co-sampled commensal organisms.
Many immune pathways key to IBD pathogenesis, highlighted by the identification of genetic variants associated with disease susceptibility, can be mapped to DCs. Nucleotide-binding oligomerization domain–containing-2 (NOD2), loss of function variants of which are associated with Crohn's disease (CD), is a bacterial sensor in DCs; its engagement impacts upon bacterial handling, cytokine production and antigen presentation (
Mouse models of colitis provide direct evidence for the importance of DCs. Transfer of bone marrow derived DCs increases inflammation whereas depletion of DCs reduces it (
DCs isolated from inflamed intestinal tissue show evidence of enhanced microbial recognition and heightened activation. More colonic cDCs from inflamed tissue of IBD patients express TLR2 and TLR4 (
In CD, more colonic LP cDCs produce IL-12/23p40 and IL-6 but the proportion of cDCs that produce IL-10 is similar to healthy controls (
MicroRNAs are short non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. Expression of microRNA (miR)-10a, which acts in DC to limit their ability to produce IL-23/23p40 and generate Th1 and Th17 responses, is reduced in the inflamed mucosa of IBD patients (
Numbers of CD103+ cDCs are reduced in mice with chronic ileitis (
RA is required for optimal Treg induction by intestinal CD103+ cDCs in the steady-state but these cells have reduced expression of RA-generating enzymes in mice with colitis (
Antibodies which target α4β7, an integrin which can be imprinted by intestinal DCs to facilitate T cell entry to the intestine, are already used to treat IBD. DCs also control the balance between regulatory and effector T cell responses in the intestine. Understanding the mechanisms involved and their regulation will facilitate rational manipulation of DCs to promote effector responses in the context of infection and vaccination or to re-establish regulation in the context of inflammatory disease.
The author confirms being the sole contributor of this work and has approved it for publication.
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.