Date Published: July 13, 2017
Publisher: Public Library of Science
Author(s): Ilona Jennifer Kosten, Rieneke van de Ven, Maria Thon, Susan Gibbs, Tanja D. de Gruijl, Chang H. Kim.
Antigen exposure to oral mucosa is generally thought to lead to immune tolerance induction. However, very little is known about the subset composition and function of dendritic cells (DC) migrating from human oral mucosa. Here we show that migratory DC from healthy human gingival explants consist of the same phenotypic subsets in the same frequency distribution as DC migrating from human skin. The gingival CD1a+ Langerhans cell and interstitial DC subsets lacked CXCR4 expression in contrast to their cutaneous counterparts, pointing to different migration mechanisms, consistent with previous observations in constructed skin and gingival equivalents. Remarkably, without any exogenous conditioning, gingival explants released higher levels of inflammatory cytokines than human skin explants, resulting in higher DC migration rates and a superior ability of migrated DC to prime allogeneic T cells and to induce type-1 effector T cell differentiation. From these observations we conclude that rather than an intrinsic ability to induce T cell tolerance, DC migrating from oral mucosa may have a propensity to induce effector T cell immunity and maintain a high state of alert against possible pathogenic intruders in the steady state. These findings may have implications for oral immunization strategies.
Dendritic cells (DC) that are located in epithelia at the interface with the outside environment form a primary barrier of defence against pathogenic intruders. They are powerful antigen presenting cells (APC), linking innate to adaptive immunity. As such they perform a delicate balancing act, maintaining immune tolerance under steady-state conditions but also inducing T cell immunity when needed. During homeostasis, migrating immature DC from peripheral tissues take up antigen but do not acquire the capacity to promote functional T cell-mediated immune responses [1,2]. However, upon their recognition through specialized receptors of pathogen- or damage-associated molecular patterns (PAMPs and DAMPs respectively), they are activated, migrate to the draining Lymph Nodes (LNs), and mature into potent immune stimulators that can drive T cell induction, expansion and differentiation [3–5].
Traditionally the oral route of antigen delivery is regarded as a sure way to induce immune tolerance. There is however a gap in our knowledge of differences in the phenotype and functionality between DC subsets of human skin and oral mucosa, which in large part will determine the outcome of T cell induction upon antigen exposure. The data provided in this manuscript are a first step towards a more detailed inventory and phenotypic and functional profiling of DC subsets in the oral mucosa, more specifically gingiva, in comparative analyses with human skin DC subsets. The skin is commonly regarded as an attractive gateway for the delivery of (tumor) vaccines whereas the oral mucosa is regarded as a gateway for the delivery of immune modulatory de-sensitization therapies e.g. hypo-sensitization sublingual immunotherapy (SLIT) [12,18–22]. It is known that DC subsets are able to migrate to draining LN, even in the steady state, and so maintain peripheral tolerance. Remarkably we found phenotypically equivalent LC and DC subsets migrating from skin and gingiva explants and in the same frequency distribution. Moreover, LC and interstitial DC subsets displayed a similar distribution between epithelium and dermis/lamina propria with, except for the CD14+ subsets, higher densities in the oral mucosa, similarly to earlier reported for oral versus nasal mucosa . As CD14+CD163+ subsets were previously identified as suppressive with the ability to expand Tregs [6,24,25], one might have expected a predominance of these subsets among gingiva-migrated DC. This however turned out not to be the case. Indeed, cytokine release profiling even pointed to a more pro-inflammatory microenvironment in the gingiva than in skin even though higher levels of the immune suppressive IL-10 were found in gingiva, IL-10 can also be produced in the context of inflammatory conditions as a feedback mechanism. Moreover, a superior ability of gingiva-emigrated DC to prime allogeneic T cells and skew them towards a type-1 functional state was observed.