Abstract
In nonobese diabetic (NOD) mice, C. rodentium promotes priming of islet-specific T-cells in pancreatic lymph nodes (PaLN), which is a critical step in initiation and perpetuation of islet-autoimmunity. To investigate mechanisms by which C. rodentium promotes T-cell priming in PaLN, we used fluorescent imaging of lymphatic vasculature emanating from colon, followed dendritic cell (DC) migration from colon using photoconvertible-reporter mice, and evaluated the translocation of bacteria to lymph nodes with GFP-C. rodentium and in situ hybridization of bacterial DNA. Fluorescent dextran injected in the colon wall accumulated under subcapsular sinus of PaLN indicating the existence of a lymphatic route from colon to PaLN. Infection with C. rodentium induced DC migration from colon to PaLN and bacterial DNA was detected in medullary sinus and inner cortex of PaLN. Following infection with GFP-C. rodentium, fluorescence appeared in macrophages and gut-derived (CD103+) and resident (CD103-/XCR1+) DC, indicating transportation of bacteria from colon to PaLN both by DC and by lymph itself. This induced proinflammatory cytokine transcripts, activation of DC and islet-specific T-cells in PaLN of NOD mice. Our findings demonstrate the existence of a direct, enteric pathogen-activated route for lymph, cells, and bacteria from colon, which promotes activation of islet-specific T-cells in PaLN.
Highlights
Microbes in the gastrointestinal tract generate immune responses which are mostly physiological and promote immune tolerance in the healthy gut[1,2]
To investigate the mechanisms by which enteric bacteria are transported to pancreatic lymph nodes, we infected mice with C. rodentium transfected with the fluorescent protein GFP and followed its appearance in colon-draining and pancreatic lymph nodes and in myeloid cells in these organs
Due to its location in the rear of peritoneal cavity, lymphatic vasculature emanating from the intestine became obscured before reaching pancreatic lymph nodes (PaLN), but accumulation of fluorescence could be clearly visualized under the capsule of PaLN (Fig. 1c insert)
Summary
Microbes in the gastrointestinal tract generate immune responses which are mostly physiological and promote immune tolerance in the healthy gut[1,2]. Distinct lymph nodes dedicated to collecting lymph and migratory DC from the colon were identified[19,20], and their role in gut immunity has thereafter been studied using powerful model systems[21]. To investigate the mechanisms by which enteric bacteria are transported to pancreatic lymph nodes, we infected mice with C. rodentium transfected with the fluorescent protein GFP and followed its appearance in colon-draining and pancreatic lymph nodes and in myeloid cells in these organs. In evidence of a lymphatic route from colon to pancreatic lymph node, which allows migration of cells and dissemination of microbes following infection with the enteric pathogen C. rodentium. This novel lymphatic route may constitute a physical link between gut dysbiosis and islet-autoimmunity
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