Ultrastructural localization of extracellular matrix proteins of the lymph node cortex: evidence supporting the reticular network as a pathway for lymphocyte migration

Abstract

BackgroundThe lymph node (LN) is a crossroads of blood and lymphatic vessels allowing circulating lymphocytes to efficiently recognize foreign molecules displayed on antigen presenting cells. Increasing evidence indicates that after crossing high endothelial venules, lymphocytes migrate within the node along the reticular network (RN), a scaffold of fibers enwrapped by fibroblastic reticular cells (FRC). Light microscopy has shown that the RN contains specific extracellular matrix (ECM) proteins, which are putative molecular "footholds" for migration, and are known ligands for lymphocyte integrin adhesion receptors.ResultsTo investigate whether ECM proteins of the RN are present on the outer surface of the FRC and are thus accessible to migrating lymphocytes, ultrastructural immunohistochemical staining of cynomolgus monkey LN was performed using antibodies to human ECM proteins that were successfully employed at the light microscopic level. The fibrillar collagens I and III were observed primarily within the reticular network fibers themselves. In contrast, the matrix proteins laminin, fibronectin, collagen IV, and tenascin were observed within the reticular fibers and also on the outer membrane surface of the FRC.ConclusionsThese findings suggest a molecular basis for how the RN functions as a pathway for lymphocyte migration within the lymph node.

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

“…It thus emerges that Nef specifically interferes with cell-motility modes that rely on the generation of contractile force to overcome physical constraints of the direct environment, including T-lymphocyte chemotaxis across transwell membranes (4,5,12,14) and diapedesis (present study). This specificity would also explain why Nef-mediated inhibition is relatively moderate on T-lymphocyte homing to spleen, which does not involve the crossing of an endothelial barrier, and motility in the lymph node parenchyma, where lymphocytes are embedded in a relatively wide-spaced extracellular matrix structure (19). In contrast, motility in the confined subendothelial space depends on the formation of sheet-like protrusions (37) that are efficiently targeted by Nef to impair cell motility.…”

“…Within the T-cell area, T lymphocytes crawl with an average speed of 15 μm/min along the 3D network of fibroblastic reticular cells and screen antigen-presenting cells for antigens. Notably, HEVs are tightly surrounded by matrix but the lymph-node parenchyma is less tightly packed with fibers as migration tracks, indicating that T lymphocytes face microenvironments with different densities during these migration steps (19). In the absence of cognate antigens, T lymphocytes exit lymph nodes within 12-24 h. Repetitive homing to and egress from lymph nodes thus requires active migration of T lymphocytes and represents a prerequisite for proper immune surveillance and screening of rare antigen-specific T lymphocytes for cognate antigen (18).…”

An Integrated Computational/Experimental Model of Lymphoma Growth

“…The temporal rate of change in viable and dead tumor tissue at any location within the tumor equals the amount of mass that is pushed, transported, and pulled due to cell motion, adhesion, and tissue pressure, plus the net result of production and destruction of mass due to cell proliferation and death:The rate of change in the volume fraction ρ i of cell species i ( V : viable tumor; D : dead tumor; H : host) is specified throughout the computational domain by balancing net creation ( S i : proliferation minus apoptosis and necrosis; see below) with cell advection (∇·( u i ρ i ), where u i is the velocity of the cell species) and cell-cell and cell-ECM interactions (adhesion, cell incompressibility, chemotaxis, and haptotaxis, incorporated in a flux J i ) [31], [32]. The reticular network within the lymph node contains a variety of extracellular matrix proteins, many of which are known ligands for integrin cell surface adhesion receptors [42], [43]. Cell-cell and cell-ECM mechanical interactions are modeled through J using a generalized Fick's Law [31].…”

Anatomy of tolerance

“…The fibers themselves provide chemotactic and/or chemorepulsive signals, which influence whether immune cells (i.e., pDC and Treg) will remain in the cortical ridge during tolerance, or migrate out of this region during an active immune response [73][74][75]. In particular, the density and geometric arrangement of stromal fibers changes in the lymph node of tolerized mice and are arranged differently compared to naive or immune lymph node.…”