Abstract
T-cell immunity in the liver is tightly regulated to prevent chronic liver inflammation in response to antigens and toxins derived from food and intestinal bacterial flora. Since the main sites of T cell activation in response to foreign components entering solid tissues are the draining lymph nodes (LN), we aimed to study whether Antigen-Presenting Cell (APC) subsets in human liver lymph-draining LN show features that may contribute to the immunologically tolerant liver environment. Healthy liver LN, iliac LN, spleen and liver perfusates were obtained from multi-organ donors, while diseased liver LN were collected from explanted patient livers. Inguinal LN were obtained from kidney transplant recipients. Mononuclear cells were isolated from fresh tissues, and immunophenotypic and functional characteristics of APC subsets were studied using flowcytometry and in ex vivo cultures. Healthy liver-draining LN contained significantly lower relative numbers of CD1c+ conventional dendritic cells (cDC2), plasmacytoid DC (PDC), and CD14+CD163+DC-SIGN+ macrophages (MF) compared to inguinal LN. Compared to spleen, both types of LN contained low relative numbers of CD141hi cDC1. Both cDC subsets in liver LN showed a more activated/mature immunophenotype than those in inguinal LN, iliacal LN, spleen and liver tissue. Despite their more mature status, cDC2 isolated from hepatic LN displayed similar cytokine production capacity (IL-10, IL-12, and IL-6) and allogeneic T cell stimulatory capacity as their counterparts from spleen. Liver LN from patients with inflammatory liver diseases showed a further reduction of cDC1, but had increased relative numbers of PDC and MF. In steady state conditions human liver LN contain relatively low numbers of cDC2, PDC, and macrophages, and relative numbers of cDC1 in liver LN decline during liver inflammation. The paucity of cDC in liver LN may contribute to immune tolerance in the liver environment.
Highlights
The liver is continuously exposed to food components and bacterial products that enter the liver from the gastrointestinal tract via the portal vein
Previous studies have shown that human lymph nodes (LN) contain two main Conventional DC (cDC) subsets which correspond to the two main cDC subsets in blood: CD141bright cDC1 and CD1c+cDC2 and [14, 38]
The present study shows that the same cDC subsets are present in liver LN
Summary
The liver is continuously exposed to food components and bacterial products that enter the liver from the gastrointestinal tract via the portal vein. Conventional DC (cDC) are the most highly specialized antigenpresenting cells (APC) and they play a critical role in the initiation and direction of T-cell responses [3, 4]. Immature cDC are located throughout most body tissues and are specialized in the uptake and processing of antigens. Under steady state conditions there is a continuous migration of antigen-loaden cDC from non-lymphoid tissues through the lymphatics toward the draining lymph nodes (LN), where they present antigens that they acquired in their tissue of origin to T cells, and this process is accelerated in response to inflammatory signals. In addition to migratory cDC, LN contain resident cDC which emerge from circulating precursors and spend their entire lives within LN, where they acquire antigens from non-lymphoid tissue that in soluble form via lymphatic drainage enter LN, and present them to T cells [6]
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