Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival

Abstract

We describe a unique extracellular matrix (ECM) niche in the spleen, the marginal zone (MZ), characterized by the basement membrane glycoproteins, laminin α5 and agrin, that promotes formation of a specialized population of MZ B lymphocytes that respond rapidly to blood-borne antigens. Mice with reduced laminin α5 expression show reduced MZ B cells and increased numbers of newly formed (NF) transitional B cells that migrate from the bone marrow, without changes in other immune or stromal cell compartments. Transient integrin α6β1-mediated interaction of NF B cells with laminin α5 in the MZ supports the MZ B-cell population, their long-term survival, and antibody response. Data suggest that the unique 3D structure and biochemical composition of the ECM of lymphoid organs impacts on immune cell fate.B-cell development | immunology S econdary lymphoid organs are characterized by their unique patterns of immune cell compartmentalization, which is important for their function. Over recent years, the molecular basis for these distinct compartments within lymph nodes and the spleen has been intensely studied, revealing a complex interrelationship between cell-cell adhesion molecules, cytokines, and chemotactic factors. Most such adhesive and chemotactic factors are expressed by the stromal cells of the nonhematopoietic scaffold of secondary lymphoid organs, which constitute the reticular fiber network. However, little attention has been given to the acellular component of the reticular fiber network, and relatively little is known about the nature of this extracellular matrix (ECM) compartment and its function. In most tissues the ECM acts to separate cellular compartments and provides scaffolds for the adhesion and migration of cells, in the form of basement membranes or fibrillar interstitial matrices; it provides molecular cues that control differentiation and proliferation processes and determines cell survival vs. cell death (anoikis), either by direct interaction with cells or indirectly due to its large potential to bind and present cytokines and chemotactic factors (1). Whether similar functions exist in secondary lymphoid organs remains largely univestigated.The reticular fiber network consists of an inner core of fibrillar collagens, ensheathed by a basement membrane layer and microfibrillar proteins, and an outer layer of reticular fibroblasts (2-4). However, the molecular constituents of these layers vary in reticular fibers of different cellular compartments, and fundamental differences exist between the lymph node and spleen (4). Apart from acting as the structural backbone and potentially also a scaffold for immigrating cells (5), the reticular fiber network functions as a conduit for small-molecular-weight (<70 kDa) soluble factors (3, 6), which, in the lymph node, permit rapid delivery of antigens and/or chemokines (5) from the periphery to the surface of high endothelial venules for recruitment of T lymphocytes (2, 3). Whether other functions exist is not clear.Our work focuses on the ECM of the splee...

Endothelial basement membrane laminin 511 is essential for shear stress response

“…The laminin α4 ( Lama4 −/− ) (Thyboll et al , 2002) and endothelial cell‐specific laminin α5 knockout mouse ( Tek‐Cre::Lama5 −/− ; Song et al , 2013) have been previously described. The Tie2 promoter drives Cre recombinase expression in the Tek‐Cre::Lama5 −/− mice and is active in all endothelial cells by E9.5 (Kisanuki et al , 2001) prior to any Lama5 endothelial expression (Sorokin et al , 1997).…”

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

“…Lymphoid conduits are ECM structures composed of a collagen core surrounded by a microfibril layer and a basement membrane creating a tube (20). The molecular composition of the lymphoid conduits varies within the functionally distinct regions of the lymphoid organs (15,(20)(21)(22), suggesting that specific ECM proteins have unique functions in regulating immune reactions. Because collagen VII is linked to cells via a laminin 332-integrin α6β4 complex, we reasoned this could also occur in spleen (26)(27)(28).…”

“…Although cues from the ECM determine functions in many organs, its role in immunity is less well understood. Evidence is emerging that the ECM in lymphoid organs, in addition to its obvious scaffold functions (12)(13)(14)(15), can also directly instruct mature immune cells (16). In this context, cochlin-an ECM protein with expression restricted to cochlea, lymph nodes, and spleen (16)-is of high interest.…”

“…The molecular composition of conduits varies between the distinct areas of the splenic white pulp (15,(20)(21)(22), pointing to differentiated roles of individual ECM components in regulating specific immune reactions (15). In response to bacterial infection, aggrecanase-mediated processing of cochlin, sequestered in the lumen of follicular conduits, leads to systemic increase of the cochlin LCCL domain.…”

Laminins affect T cell trafficking and allograft fate

“…Laminin-511 contains the laminin α5 chain and fails to promote T cell migration, although T cell costimulatory properties have been reported (33). Recent work suggests the presence and ratio of these laminin isoforms may dictate inflammatory responses and maturational niches for T and B cells (36,37), although how they are regulated has not been investigated.…”