disrupting the bacterial inner membrane.6 Additionally, some antimicrobial proteins can function by depriving bacteria of essential heavy metals, such as iron.7 One of the best characterized mucosal antimicrobial peptides is RegIIIγ. This lectin is expressed soon after birth or following colonization of germfree mice.8 Production of RegIIIγ is tightly controlled by the flora in an MyD88-dependent manner and has a direct microbicidal effect on gram-positive bacteria.8,9,10 Similarly, the PRR nucleotide-binding oligomerization domain-containing protein (NOD) 2 controls expression of a subset of α-defensins and cryptdins by Paneth cells.11 Critically, antimicrobial proteins are retained in the mucus layer and are virtually absent from the luminal content.12 Such a feature allows antimicrobial activity to be concentrated within a region bordering the epithelial cell layer. Recent findings demonstrate that the accumulation of RegIIIγ in the mucus contributes to the maintenance of the segregation between the microbiota and the host intestine.13
TABLE 34.1 Subsets of Intraepithelial Lymphocytes in Mice and Humans
their cluster of differentiation (CD)8 expression with a large fraction expressing CD8αα (see Table 34.1).75
literature, the current consensus is that CD103+ cells are mucosal DCs with capacity to rapidly migrate into lymphoid structures, whereas the CX3CR1+ populations are considered to be tissue resident macrophages.113 The gut also contains a minor population of CD103+CD11b-CD8α+CX3CR1-DCs believed to be associated with ILFs.114 Additionally, the gut is home to plasmacytoid DCs.115 APC subset distribution varies anatomically with CD103+CD11b+ DCs mostly represented in the duodenum and CD103-CD11b+ DCs enriched in the large intestine.116
antigens and bacteria can gain access to DCs in the LP. This can occur by trans- or paracellular transport or by receptormediated trafficking, such as occurs through the neonatal FcR expressed on absorptive epithelial cells in humans.131 Luminal antigens can also be directly sampled by mucosal DCs. Indeed, subepithelial DCs can penetrate the epithelium monolayer by extending dendrites into the lumen, allowing them to sample particles and bacteria.132,133,134 In the terminal ileum, this process is tightly dependent on the fractalkine receptor CX3CR1 and controlled by the microbiota in an MyD88-independent manner.132,133,135 In addition to CX3CR1, CCL20 can also contribute to transepithelial dendrite formation.133 Luminal antigen can gain access to mucosal sites by direct damage to the epithelium, as can occur during IBD or in response to infection with HIV136 or Shigella flexneri.137 Antigen sampling may also occur by uptake of exosomes from epithelial cells or across villous microfold cells.138 Even in the absence of infection or inflammation, LP DCs constitutively traffic to MLN,139 which appears to be a relatively active process. These migratory DCs can carry self- or cell-associated antigens from apoptotic epithelial cells140 or soluble proteins given orally.141 Soluble antigens given orally can be processed by LP DCs, which then migrate to the MLN in a CCR7-dependent manner.142 Various lines of evidence support the idea that CD103+ DCs have enhanced migratory capacity to lymphoid structures compared to other mucosal MP subsets. Indeed, CD103+ DCs are highly represented in the gut afferent lymphatics,119 constitutively migrating to the MLN at steady state, and are the first to reach the MLN under inflammatory conditions.113,119 In response to inflammation, various signals including lipopolysaccharides and flagellin can influence the capacity of mucosal DCs to transport intestinal commensals and pathogenic bacteria to the MLN.143,144 A remarkable feature of this process is that commensal loaded LP DC migration is restricted to the mucosal immune compartment by the MLN.143 Such a process is believed to contribute to the compartmentalization of mucosal immune responses. Although as further discussed, mucosal MP can promote the induction of tolerance under steady-state conditions, the function of these cells is highly contextual, and under inflammatory settings mucosal MP can rapidly adopt a highly inflammatory phenotype and induce effector responses.145
FIG. 34.2. Metabolism and Major Cellular Sources of Retinoic Acid (RA). Dietary vitamin A is absorbed in the intestine and transported through the lymphatics into the circulation where it enters the liver for storage. Retinol chaperoned by retinol binding protein is constitutively deployed from the liver into circulation. It is also secreted in bile that drains into the small intestine. Upon entry into cells, retinol is reversibly oxidized into retinal via the alcohol dehydrogenase enzyme family. Depending on the cell type (see Table 34.1), retinal can undergo irreversible metabolism into RA via retinal dehydrogenases (RALDH). Table 34.1 provides an overview of major cellular sources of RA at steady state including cellular location, the isoform(s) of RALDH that are expressed, and the factors known to induce RALDH expression in each cell type.
bone marrow-derived DCs via inhibition of suppressor of cytokine signaling 3 activity.192 These findings suggest interdependency between TGF-β- and RA-propagated signals in several cell lineages.
regulatory activities. Under homeostatic conditions, the coordinated action of these cells results in the induction of regulatory responses toward dietary or commensal derived antigens.
FIG. 34.4. Induction of Foxp3+ Regulatory T (Treg) Cells at Mucosal Sites. Under steady-state conditions, cluster of differentiation (CD)103+ dendritic cells (DCs) uptake directly or indirectly commensals and dietary antigens, and constitutively migrate to the mesenteric lymph node (MLN). In the MLN, based on their capacity to metabolize vitamin A (retinaldehyde dehydrogenase) and produce retinoic acid (RA) and to activate transforming growth factor (TGF)-β (α(v)β8+); CD103+ DCs induce Foxp3+ Treg cells from naïve T cells. Exposure to RA induces gut homing receptor CCR9 and α4β7 that allows the migration of these cells to the gut mucosa. In the gut, Foxp3+ Tregs can be expanded by CX3CR1 macrophages in an interleukin-10-dependent manner. At mucosal sites, inducible Tregs and thymically derived Tregs can limit a range of effector responses directed against dietary or commensal-derived antigens. Further, Treg cells in a TGF-β-dependent manner can also promote immunoglobulin A responses that in turn limit contact with the microbiota.
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