Unique Transcompartmental Bridge: Antigen-Presenting Cells Sampling across Endothelial and Mucosal Barriers

Abstract

Potentially harmful pathogens can gain access to tissues and organ systems through body sites that are in direct contact with the outside environment, such as the skin, the gut, and the airway mucosa. Antigen-presenting cells (APCs) represent a bridge between the innate and adaptive immunity, and their capacity for constant immune surveillance and rapid sampling of incoming pathogens and other potentially harmful antigens is central for mounting an effective and robust protective host response. The classical view is that APCs perform this task efficiently within the tissue to sense invading agents intra-compartmentally. However, recent data based on high resolution imaging support an additional transcompartmental surveillance behavior by APC by reaching across intact physical barriers. In this review, we summarize intravital microscopic evidences of APC to sample antigens transcompartmentally at the gut mucosa and other body sites.

Keywords: T cell activation; antigen capture; antigen presentation; antigen-presenting cell; cell migration; dendritic cell; mucosal immunity; transcompartment.

Figure 1

Different models of TE and antigen uptake by LP APC. LP APCs adjacent to the villus epithelia extend finger-like projections or balloon bodies (BB) directly into the gut lumen to sample microbes. Both CD11c⁺CX3CR1⁺CD103⁻ Macs and CD11c⁺CX3CR1⁻CD103⁺ DCs have been shown to push TEs into intestinal lumen to directly interact with pathogens. CD11c⁺MHC-II⁺ DCs have been visualized to extend BBs into the lumen in some explant preparations. Tight junction proteins expressed by LP APCs allow preservation of villus epithelia organization. CD103⁺ DCs closer to the villus core may receive antigen from goblet cells and/or CX3CR1⁺ Macs or may directly sample translocated pathogens/antigens themselves before migrating to the draining mesenteric LN. CD11c⁺CX3CR1⁺MHC-II⁺CD11b⁻ phagocytes have also been shown to unidirectionally translocate into the lumen to participate in pathogen exclusion.

Figure 2

Overview of LN APC positioning for TE sampling. A cartoon of the LN depicting the various APC extensions into or in direct contact with the subscapular sinus, medullary sinus, B cell zone LN conduits, high endothelial venules, and paracortical zone LN conduits [adapted from Girard et al. (40)].

Figure 3

Activated DCs reside near HEV after migrating from the periphery. Single 0.5 μm optical section from an intravital 2PLSM experiment showing the perivascular juxtaposition of migrating DC (blue) from the periphery and the high endothelial venule (HEV; light green) in the LN. Newly i.v. injected T cells (deep bright green) can be seen attaching to the luminal wall as well as migrating in the LN parenchyma through the HEV structure (Alex Y. Huang). Intravital 2PLSM of mouse LN was performed under a protocol approved by the Case Western Reserve University IACUC.

Figure 4

LN DCs and Macs extend processes into the medullary sinus to directly sample lymph-borne antigen. An expanded cartoon of the LN medullary sinus from Figure 2, depicting DCs, subcapsular, and medullary sinus macrophages embedded into the medullary sinus floor and contacting naive T cells [adapted from Gerner et al. (50)].

Figure 5

Lung DCs sample airway pathogens via TEs. A cartoon of the airway leading into the alveolar space, showing alveolar tissue-resident DCs extending their processes into the air canal between tight junctions of the alveolar epithelial cells to contact pathogens under steady-state conditions [adapted from Hammad et al. (60)].