Antigen archiving by lymph node stroma: A novel function for the lymphatic endothelium

Abstract

Secondary lymphoid stroma performs far more functions than simple structural support for lymphoid tissues, providing a host of soluble and membrane-bound cues to trafficking leukocytes during inflammation and homeostasis. More recently it has become clear that stromal cells can manipulate T cell responses, either through direct antigen-mediated stimulation of T cells or more indirectly through the retention and management of antigen after viral infection or vaccination. In light of recent data, this review provides an overview of stromal cell subsets and functions during the progression of an adaptive immune response with particular emphasis on antigen capture and retention by follicular dendritic cells (FDC) as well as the recently described “antigen archiving” function of lymphatic endothelial cells (LEC). Given its impact on the maintenance of protective immune memory, we conclude by discussing the most pressing questions pertaining to LEC antigen capture, archiving and exchange with hematopoetically derived antigen-presenting cells.

Regulation of germinal center B‐cell differentiation

“…While a substantial proportion of antigen is recycling, 60% of antigen is not recycling within 3 h . FDC can hold intact antigen in the form of immune complex for many months . The presence of a second intracellular reservoir may be important, as it may represent a protected habitat where antigen is held for prolonged periods, possibly occasionally presented to reactivate B cells over sustained periods.…”

Molecular tracking devices quantify antigen distribution and archiving in the lymph node

“…Fibroblasts and non-endothelial stromal cells comprise a large portion of the lymph node stroma and are capable of presenting peripheral tissue antigens, but their capacity to acquire and present foreign antigens is not yet well understood 28,29,30 . We were unable to detect antigen archiving by blood endothelial cells or fibroblasts in our initial studies 12,13 . While LECs have been shown to present antigens in the absence of inflammation to induce T cell tolerance 31,32,33,34,35,36,37,38 , we showed that presentation of archived antigen occurs only after exchange of the archived antigen from an LEC to a migratory DC; changing the stimulus from tolerizing to immunostimulatory 12,13 .…”

“…We were unable to detect antigen archiving by blood endothelial cells or fibroblasts in our initial studies 12,13 . While LECs have been shown to present antigens in the absence of inflammation to induce T cell tolerance 31,32,33,34,35,36,37,38 , we showed that presentation of archived antigen occurs only after exchange of the archived antigen from an LEC to a migratory DC; changing the stimulus from tolerizing to immunostimulatory 12,13 . Soluble antigens are exchanged via two distinct mechanisms: (i) direct exchange between LECs and migratory DCs and (ii) LEC death.…”

“…Previous studies have shown that viral antigens persist in the lymph node beyond the time frame of infectious virus 6,7,8,9,10,11 . We recently found that lymphatic endothelial cells (LEC) store antigens from viral infection and vaccination 12,13,14 . Using a vaccine formulation that elicits robust cell-mediated immunity comprised of antigen, a Toll-like receptor (TLR) agonist, and an agonistic aCD40 antibody (TLR/aCD40 vaccination) or viral infection 15,16,17,18,19,20,21,22,23,24,25,26 , we discovered that antigens were durably retained in the lymph node 12,13,14 .…”

Immunoregulatory Effects of Neuropeptides on Endothelial Cells: Relevance to Dermatological Disorders

“…These include not only the recruitment and delivery of inflammatory cells to the skin, but also the release of cytokines and chemokines. Additionally, endothelial cells are present in secondary lymphoid organs [1], including skin-draining lymph nodes, and have immunoregulatory effects at those sites [2]. Blood vessels in the skin are intimately associated with sensory and sympathetic nerves as are the secondary lymphoid organs [3-5].…”