Uptake of Antigens from the Intestine by Dendritic Cells

75

Ann. N.Y. Acad. Sci. 1029: 75–82 (2004). © 2004 New York Academy of Sciences.doi: 10.1196/annals.1309.010

Uptake of Antigens from the Intestine by Dendritic Cells

GORDON MACPHERSON,a SIMON MILLING,a ULF YRLID,a LESLEY COUSINS,a EMMA TURNBULL,b AND FANG-PING HUANGc

aSir William Dunn School of Pathology, University of Oxford, Oxford, United KingdombEdward Jenner Institute for Vaccine Research, Berkshire, United KingdomcDepartment of Pathology, University of Hong Kong, Hong Kong

ABSTRACT: The intestinal immune system responds to ingested antigens in avariety of ways, ranging from tolerance to full immunity. How T cells areinstructed to make these differential responses is still unclear. Dendritic cells(DCs) sample enteric antigens in the lamina propria and Peyer’s patches, andtransport them within the patch or to mesenteric nodes where they are present-ed to lymphocytes. It is probable that DCs also transmit information thatinfluences the outcome of T cell activation, but the nature of this informationand the factors in the intestine that regulate DC behavior and properties arefar from clear. We have developed a model in the rat that permits analysis ofDCs actually in the process of migration from the intestine to mesenteric nodes.In this paper we will review those aspects of our research that relate to antigenuptake and discuss these in the context of other experimental systems.

KEYWORDS: dendritic cell; antigen uptake; rat; lymph; lymph node; intestine;Peyer’s patch; scrapie; prions; TSE; migration

INTRODUCTION

Naive CD4+ T cells represent an immunological example of middle management.They have been educated and selected (thymus), but they move around randomlyuntil told what to do (secondary lymphoid tissues). They can react in a variety ofways to instruction (tolerance, regulation, Th1, Th2), but in general they cannot dovery much on their own (effector function); they have to tell others what to do.Understanding the regulation of CD4+ T cell activation and differentiation is, how-ever, crucial to understanding how to harness and modulate intestinal immuneresponses for therapeutic purposes. It is increasingly clear that dendritic cells (DCs)play central roles in these processes and, thus, understanding the biology of intesti-nal DCs is of major importance in these areas.

The intestine encounters a huge variety of antigens, mostly harmless under nor-mal circumstances. Some, however, are inherently pathogenic, whereas others can

Address for correspondence: Dr. G. Gordon MacPherson, Sir William Dunn School of Pathol-ogy, University of Oxford, UK. Voice: +44-1865-275584; fax: +44-1865-275501.

[email protected]

76 ANNALS NEW YORK ACADEMY OF SCIENCES

become pathogenic if an inappropriate immune response is initiated, for example, togluten in celiac disease or commensal bacteria in models of inflammatory bowel dis-ease (IBD). It is likely that small proportions of all ingested proteins are absorbedintact and will thus interact with the adaptive immune system, either in Peyer’spatches (PPs) or mesenteric nodes (MLN), and, thus, mechanisms must exist thatdetermine how lymphocytes exposed to antigens subsequently differentiate: whetherthey induce active immunity, become unresponsive (tolerance), or become able todownregulate the activation of other naive, antigen-specific cells (regulation).

Sites of lymphocyte activation, apart from PPs, are anatomically distant from thesites of antigen entry, and even in PP, T cells are activated in areas to which antigenmay not have direct entry. T cells, however, respond differentially to nonpathogenicand pathogenic antigens, and the types of active response that are initiated can showdistinct polarization. For example, intestinal Trichinella induces a strong, protectiveTh2 immune response in rodents, whereas Eimeria induces a strong, protective Th1response. These two parasites illustrate very clearly one of the central problems inintestinal immunity. Thus, in the early stages, at least, both are confined to the intes-tine, but the response to them is initiated in the MLN.1 Not only must antigen betransported from the intestine to MLN, in addition, information must reach naive Tcells that informs their differentiation pathways. We are still far from having a com-plete understanding of either of these processes; yet such an understanding is crucialif we are to develop effective intestinal vaccines and strategies for the immunother-apy of IBD and food hypersensitivities.

Increasing evidence suggests that DCs play a central and crucial role in bothantigen uptake and delivery, and in regulating the outcomes of T cell activation. Thispaper will review the roles of intestinal DCs in the uptake, transport, and delivery offoreign antigens introduced into the intestinal lumen and of self-antigens in the formof apoptotic cells and will be based largely on our studies in the rat.2–11

DENDRITIC CELLS

DCs include several distinct subpopulations that differ in life history and func-tions.12 The complexity of these cells is apparent, but unraveling the significance ofthis complexity is beset with difficulties: DCs are rare cells, difficult to isolate; theycan exist at different stages of maturation and activation; and their isolation itself caninduce changes in gene expression, phenotype, and function. In addition, it is prov-ing difficult to relate DC subpopulations in rodents to their human counterparts.

DCs in the adult are mostly bone marrow derived, although murine Langerhanscells are self-renewing in the steady state.13 However, the points at which DClineages branch from other hemopoietic lineages are ill defined. Thus, murine DCsmay have a CD11c blood precursor,14 but under inflammatory conditions can derivefrom monocytes.15

INTESTINAL DENDRITIC CELLS

Intestinal DCs have been isolated from intestinal lamina propria of mice,16

humans,17–19 and rats.7 They have also been isolated from PPs of the same and other

77MACPHERSON et al.: UPTAKE OF ANTIGENS

species.7,20–38 The isolation of DCs from the lamina propria is, however, inefficient(the proportion of DCs present that is actually isolated is unknown, but probablyvery small), may select for particular subsets, and can induce at least partial activa-tion. In addition, such DCs represent cells at different stages of maturation. To com-pensate for these difficulties, we have developed a model that permits collection ofDCs that are in the process of migration from the intestine to the MLN.

PSEUDOAFFERENT LYMPH DENDRITIC CELLS

DCs migrating in lymph from the intestine are normally extracted efficiently inthe mesenteric nodes (>95%) and do not appear in significant numbers in efferentlymph.39 If the MLN are removed in young rats, afferent and efferent lymphaticsheal, permitting passage of DCs into the thoracic duct, from which they can be col-lected by insertion of a cannula. These cells can be collected over at least 48 h,placed on ice to “freeze” them metabolically, and purified by different combinationsof density gradient centrifugation, magnetic bead sorting, and flow cytometric sort-ing (FACS). These DCs have only just left the intestine, are the ones involved in an-tigen transport and delivery, and are probably the ones that regulate T celldifferentiation. They represent DCs “in action.” We have characterized these DCs indetail.2–6,8,9,40 Important findings from our lab include the following:

DCs are migrating continually from the intestine in the absence of any overt stim-ulation, as is in fact true for all peripheral tissues studied. In rats, DC output is main-tained at a relatively constant rate for at least five days after cannulation.2 Intestine-derived DCs can be found in T cell areas of MLN from germ-free rats,10 showingthat their migration is not dependent on commensal flora.

At least two distinct populations of DCs migrate from the intestine.41 CD4+/SIR-Pα+ DCs resemble ”classical” DCs and are strong antigen-presenting cells (APCs).In contrast, CD4−/SIRPα− DCs are weaker APCs, survive very poorly in culture, butcarry remnants of apoptotic enterocytes to T cell areas of MLN,10 and, thus, may beinvolved in constitutive presentation of self antigens to induce tolerance (see below).It is of interest that similar DC subpopulations are present in bovine skin lymph.42

DENDRITIC CELLS AND SELF-TOLERANCE

Several reports suggest that DCs play a crucial role in tolerance to peripheral self-antigens and, by analogy, to nonpathogenic intestinal antigens. Thus, IgG or a henegg lysozyme peptide targeted to DCs in mice induces tolerance,43,44 and a truncat-ed, nonsecreted form of ovalbumin (OVA), expressed solely in enterocytes, inducestolerance in TCR transgenic CD8+ T cells.45 More direct evidence that DCs are thecell type involved in self-tolerance comes from studies of tolerance to pancreaticislet-expressed OVA, where CD8α+ DCs from pancreatic nodes were shown to beable to present OVA to T cells.46


UPTAKE OF ANTIGENS BY INTESTINAL DENDRITIC CELLS

Soluble Antigens

Soluble antigens introduced into the intestine can induce specific hyporespon-siveness in T lymphocytes (oral tolerance). We have shown that after giving antigenby gavage or direct injection into the intestine at laparotomy, DCs collected frompseudoafferent lymph between 6 and 18 to 24 h can present the antigen specificallyto sensitized T cells in vitro.5 More recently, we have found that following the injec-tion of FITC-labeled OVA intraintestinally, FITC can be detected in 4 to 6% of lymphDCs between 6 and 18 h after injection. Both CD4+/SIRPα+ and CD4−/SIRPα− DCsexpressed fluorescence in approximately similar proportions, but in the former, thefluorescence had a fine granular appearance, whereas in the latter it was concentrat-ed in large inclusions. We do not know whether DCs in which fluorescence could notbe detected were devoid of antigen.

Particulate Antigens

The major portals of entry for particulate antigens are PPs, via M cells. Virus-sized latex particles given by gavage to mice are taken up by subepithelial dome DCsand remain in these cells for at least 14 days.47 We have done similar experiments inrats using a variety of latex particles and were surprised to find virtually no translo-cation into PPs. Possibly this relates to the specific pathogen-free (SPF) status of ourrats, as it has been shown that moving mice from SPF to conventional conditionsstimulates a three-fold increase in M cell numbers.48 An alternative mechanism forparticulate transport has been suggested by Rescigno et al. They found that intralu-menal bacteria could induce lamina propria DCs to extend processes between epi-thelial cells, and suggest that these processes can capture and translocate bacteria.49

Some pathogens, such as Eimeria and Trichinella, are confined to the intestine,at least in the early stages of infection, yet both induce strong immunity which, forTrichinella at least, commences in MLN.50 Essentially, nothing is known about howantigens from these parasites are transported to the nodes.

UPTAKE OF PRION PROTEINS FROM THE INTESTINE

The protease-resistant form of prion-related protein (PrP), PrPSc, is thought to bethe agent responsible for transmissible spongiform encephalopathies (TSEs). PrPSc

accumulates in the central nervous system of infected individuals and is thought tobe transmitted largely by consumption of infected material. PrPSc contains a largeproportion of β-pleated sheets and aggregates spontaneously. The form that is ab-sorbed from the intestine is not known, but it may well be handled as a particle ratherthan a soluble protein. Scrapie is a form of TSE that has been adapted to murinemodels. Following peripheral administration, PrPSc in the form of scrapie-associatedfibrils (SAF), accumulates/replicates in secondary lymphoid tissues in or on follic-ular dendritic cells (FDC).51 FDC are resident, long-lived cells in B cell follicles andare unrelated to the migratory DCs so far discussed. We suggested that DCs mightacquire PrPSc from the intestine and transport it to mesenteric nodes. To test this, we


injected mesenteric-lymphadenectomized cannulated rats with SAF and examinedlymph at intervals afterwards.11 PrP could be detected by immunolabeling in 4 to 6%of DCs between 6 and 24 h after injection. Immunoblotting showed that at least aproportion was protease resistant. PrP could not be detected in any other lymph cells,in lymph plasma, or in DCs from noninjected rats. Scrapie infectivity is tested by in-tracerebral injection into mice. Injection of lysates from DCs collected from intesti-nally injected rats did not, however, reveal significant infectivity. This probablyrelates to the very small amounts of PrPSc acquired by DCs (about 1 in 10,000 of themolecules injected).

PrPSc is rapidly degraded in macrophages.52 We, however, had evidence that DCscould retain native protein antigens for long periods. Thus, following briefincubation of splenic DCs with horse radish peroxidase, active enzyme could bedetected for over 24 hours.53 In addition, when splenic DCs were isolated from ratsup to 24 h after giving protein intravenously, injection of these DCs into naive ratsstimulated an antibody response, showing that the transferred DCs contained intactantigen.53,54 Recently, we have found that PrPSc accumulates similarly in DCs andmacrophages during in vitro coincubation, but that the agent is rapidly degraded inmacrophages, whereas immunodetectable PrPSc is retained for at least 72 h in DCs(Huang et al, in preparation).

DELIVERY OF ANTIGEN TO LYMPH NODES

How the antigens that are inducing tolerance or immunity are actually deliveredto T cells is unclear. Molecules such as chemokines injected subcutaneously or intothe intestinal wall rapidly enter lymph, but the great bulk of such molecules are ex-cluded from the T cell areas of the draining nodes.55–58 The lymph node cortex con-tains numerous channels that run from the subcapsular sinus to high-endothelialvenules, and these serve as conduits for such molecules. Recent studies have shownthat following subcutaneous injection of antigen, two waves of antigen appear in thenode. The first appears rapidly in the conduits and labels T cell area DCs weakly.The second wave is delayed by several hours, and the antigen appears in strongly la-beled DCs. This second wave and, crucially, sensitization for delayed-type hyper-sensitivity, is abolished by extirpating the antigen depot, suggesting that the labeledDCs had acquired antigen in the periphery and then migrated to the node.59,60 It isnot known whether the first wave of antigen can induce tolerance.

CONCLUSIONS

The mechanisms by which adaptive immune responses to intestinal antigens areregulated are as yet poorly understood. In the steady state, DCs are continuallymigrating from the intestine to MLN, carrying self- and food antigens, and duringinfection, they presumably carry antigens from intestinal pathogens. DCs representthe main mechanism by which antigen is transported and delivered to T cells, butDCs represent complex cell populations with different functions. DCs are recruitedrapidly to inflamed tissues, and their properties may be modulated by cytokinesreleased in these tissues. This modulation of DC properties may be central to induc-


ing differential activation pathways in T cells, but, as yet, little is known about whatis really going on under these circumstances in the periphery and in the node.Understanding these processes is, however, crucial to devising rational vaccinationand immunotherapeutic strategies in the future.

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Uptake of Antigens from the Intestine by Dendritic Cells