Research Article

Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesicles

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Science  09 Nov 2018:
Vol. 362, Issue 6415, eaao0666
DOI: 10.1126/science.aao0666

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Dendritic cells give mast cells a nudge

Anaphylaxis is a life-threatening allergic reaction triggered after antigen-specific immunoglobulin E (IgE) antibodies bind to target allergens. These antibodies then cross-link IgE-specific Fc receptors on the surface of mast cells. The mast cells rapidly release inflammatory mediators, including histamine, resulting in smooth muscle contraction, vasodilation, and blood vessel leakage. Because mast cells are usually found in the perivascular abluminal surface of blood vessels, it has been unclear how blood-borne allergens can interact with them. Choi et al. used live intravital imaging of the mouse vasculature to show that a specialized subset of dendritic cells sample blood-borne antigens and relay them to mast cells on the surface of microvesicles (see the Perspective by Levi-Schaffer and Scheffel). IgE-bound mast cells then vigorously degranulate after contact with these microvesicles.

Science, this issue p. eaao0666; see also p. 640

Structured Abstract


An increasing number of individuals suffer from acute anaphylaxis, particularly food-associated reactions. The symptoms of anaphylaxis are triggered soon after allergens (such as peanut antigens, insect venom, or certain medications) enter the circulation of sensitized subjects who have elevated levels of antigen-specific immunoglobulin E (IgE) antibodies in their circulation. Mast cells (MCs) are the primary effectors of anaphylaxis and become activated when allergens make contact with IgE antibodies bound to the surfaces of MCs. Upon activation, MCs rapidly release prestored inflammatory mediators. When this occurs simultaneously throughout the body, anaphylaxis and shock result. As MCs are typically found in the perivascular abluminal surface of relatively impregnable blood vessels, how these cells perceive and interact with blood-borne allergens is unclear.


Extravascular MCs were recently reported to be capable of extending cellular protrusions to directly sample vascular contents. Therefore, we reasoned that if MCs are directly sampling the blood, we should find that MCs are the first cells to acquire allergens upon systemic infusion of labeled allergen. We systemically infused mice with labeled dextran and examined which immune cells in the proximity of the vasculature had acquired the label within 30 min of antigen administration.


Surprisingly, MCs acquired only a small number of the dextran particles. Instead, most of the labeled antigen was acquired by a subset of dermal dendritic cells (DCs). These DCs, defined as CD301b+ dermal cDC2, were found in close proximity to MCs in the perivascular abluminal surface lining dermal blood vessels. Furthermore, they appeared to directly sample the blood through the extrusion of dendrites. These DCs were critical to anaphylaxis, as IgE-sensitized mice deficient in CD301b+ dermal cDC2 failed to undergo anaphylaxis. Live microscopy of the mouse vasculature revealed numerous perivascular DCs routinely sampling blood-borne allergens via dendrites, which penetrated the endothelial wall into the vascular lumen (left panel in the figure). Blood-borne antigens captured in this manner were relayed on the surfaces of 0.5- to 1.0-μm microvesicles (MVs) to neighboring MCs and DCs in the perivascular space. A panoply of receptors can be found on the surfaces of DCs, including the mannose receptor, which enable these cells to capture a broad range of foreign antigens in the blood. Knocking down mannose receptors markedly reduced the capacity of DCs to bind antigen and convey antigen to MCs. Furthermore, large numbers of MVs were constitutively shed by DCs regardless of whether contact with antigens was made. MVs were products of specific budding and pinching-off activities occurring on the plasma membranes of DCs. Additionally, MV shedding was abrogated when vacuolar protein sorting–associated protein 4 (VPS4), which mediates scission of MVs, was knocked down. DCs impaired in their ability to express VPS4 were found to be incapable of activating MCs or causing anaphylaxis. Noticeably, distribution of antigens by DCs on budding MVs occurred relatively quickly and was not preceded by internalization of antigen. Upon contact with allergens on the surfaces of MVs, IgE-bound MCs were found to degranulate vigorously, releasing their payload of inflammatory mediators (right panel in the figure) and triggering anaphylaxis. Thus, allergen-induced MC degranulation and anaphylaxis require the critical contribution of perivascular DCs in capturing and relaying circulating allergens.


We demonstrate how IgE-sensitized MCs are indirectly activated by blood-borne allergens. Additionally, our study reveals how perivascular DCs continuously sample blood and initiate and markedly enhance inflammatory and immune responses by rapidly discharging antigen-bearing MVs to surrounding immune cells.

Transfer of blood-borne allergens by DCs to MCs during anaphylaxis.

(A) Sampling of blood-borne allergens by perivascular DCs. (B) Relaying of allergens borne on vesicles to neighboring MCs and DCs. Ag, antigen; dDC, dermal DC.


Anaphylactic reactions are triggered when allergens enter the blood circulation and activate immunoglobulin E (IgE)–sensitized mast cells (MCs), causing systemic discharge of prestored proinflammatory mediators. As MCs are extravascular, how they perceive circulating allergens remains a conundrum. Here, we describe the existence of a CD301b+ perivascular dendritic cell (DC) subset that continuously samples blood and relays antigens to neighboring MCs, which vigorously degranulate and trigger anaphylaxis. DC antigen transfer involves the active discharge of surface-associated antigens on 0.5- to 1.0-micrometer microvesicles (MVs) generated by vacuolar protein sorting 4 (VPS4). Antigen sharing by DCs is not limited to MCs, as neighboring DCs also acquire antigen-bearing MVs. This capacity of DCs to distribute antigen-bearing MVs to various immune cells in the perivascular space potentiates inflammatory and immune responses to blood-borne antigens.

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