Circulatory Antigen Processing by Mucosal Dendritic Cells Controls CD8+ T Cell Activation

Abstract

Circulatory antigens transit through the small intestine via the fenestrated capillaries in the lamina propria prior to entering into the draining lymphatics. But whether or how this process controls mucosal immune responses remains unknown. Here we demonstrate that dendritic cells (DCs) of the lamina propria can sample and process both circulatory and luminal antigens. Surprisingly, antigen cross-presentation by resident CX3CR1+ DCs induced differentiation of precursor cells into CD8+ T cells that expressed interleukin-10 (IL-10), IL-13 and IL-9 and could migrate into adjacent compartments. We conclude that lamina propria CX3CR1+ DCs facilitate the surveillance of circulatory antigens and act as a conduit for the processing of self- and intestinally-absorbed-antigens, leading to the induction of CD8+ T cells, that partake in the control of T cell activation during mucosal immune responses.

Lymphatic transport of high-density lipoproteins and chylomicrons

“…That the fenestrated blood vessels lie atop the lacteal around much of its exposed surface likely contributes to ensuring that smaller molecules, including hydrophilic nutrients and antigens not packaged in chylomicrons, primarily access the blood vasculature for transport, although there is a certain probability that a portion of these small molecules bypasses the fenestrated vasculature and enters the lymph (Figure 1), consistent with experimental observations. Furthermore, the rich macrophage and DC network in intestinal villi acquires many macromolecules that enter intestinal villi through robust endocytosis (65). Their collective endocytic activity protected the lacteal from absorption of tracer antigens, whereas depletion of these cells allowed increased absorption into the lacteal, with a resulting shift in the ensuing immune response (65).…”

“…Furthermore, the rich macrophage and DC network in intestinal villi acquires many macromolecules that enter intestinal villi through robust endocytosis (65). Their collective endocytic activity protected the lacteal from absorption of tracer antigens, whereas depletion of these cells allowed increased absorption into the lacteal, with a resulting shift in the ensuing immune response (65). The study did not investigate whether the presence of macrophages and DCs affected chylomicron absorption or absorption of other nutrients.…”

Differentiation of CD11c + CX 3 CR1 + cells in the small intestine requires Notch signaling

“…S3C), indicating that the R5 population is almost identical to CD11c low CX 3 CR1 + cells. A previous study revealed that the R3 population secretes IL-10, which is involved in the low T-cell-stimulatory activity of this population (25,26). We tested the mRNA expression of Il10 in R1-R4 populations from control mice and in the R5 population from Rbpj −/− mice.…”

Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells

“…8,35 To test for uptake of systemically delivered protein antigen in the gut, Alex Fluor 647-labeled ovalbumin was intravenously injected and found to be taken up by F4/80 1 and CD11c 1 cells in the ileum (supplemental Figure 11). 36 …”