Lymph node stromal cell

Lymph node stromal cells are involved in formation the lymph node. These cells interact with hematopoetic cells and they also provide the scaffold for them. They remain express molecule which common for all stromal cells. But they express a lot of other special small molecules such as adhesive molecules, chemokines and cytokines for them. They facilitate migration and contact between hematopoetic cells and antigens and they participate in the initiation of an adaptive immune responses.

Lymph node

Lymph nodes together with the spleen and Peyer‘s plates belong to secondary lymphoid organs. Lymph node occurs at the interface between lymphatic and blood vessels. Blood artery leads naive lymphocytes from thymus and bone marrow into the lymph node. Lymphocytes permeate through blood endothelial cells (BECs). Lymphocytes now interact with fibroblast reticular cells (FRCs) and move along a reticular network to appropriate areas of the lymph tissue. Lymphocytes are coming into place by chemokines, which are produced by stromal cells. The level and type of chemokines determine certain areas of the lymph node, and the type of stromal cells. Afferent lymphatic vessels bring a lymph from peripheral tissues into the lymph node. The lymph contains plenty of soluble antigens and antigen presenting cells (APCs) with presented antigens. Antigens stimulate T and B lymphocytes in the lymph nodule cortex. Lymphocytes differentiate into effector T lymphocytes or plasma cells, and they are transferred to a medulla. Here these cells enter through the terminal sinus into the efferent lymphatic vessel, which take cells to the superior lymph node.

Structure of the lymph node

The lymph node is enclosed in a fibrous capsule, it penetrate into the interior by the septum (trabeculae), which partially divide the lymphatic tissue. The lymph tissue consist of immune cells (95 %) and stromal cells (5 %). The entire space is filled nodules network of reticular fibers. Under the fibrous tissue are located peritrabecular and subcapsular sinuses. Sinus is a set of cavities filled with lots of macrophages. The interior of the lymph node is distinguished the cortex from the medulla, which contain reticular network and hematopoietic cells. In the cortex, lymphoid tissue is organized into lymph nodules, where T lymphocytes fill the reticular network called the T cell zone and B lymphocytes are accumulated in an area called the B cell follicle. The primary B cell follicle matures in a germinal center. Areas differ not only cell type, but also the type of stromal cells. The medulla contains effector T cells, plasma cells and DCs. Near the medulla is located an area known as hilum. This is the place where blood vessels and efferent lymphatic vessel enter and leave the lymph nodes. Afferent lymph vessels enter along the perimeter of the lymph node.

Types of lymph node stromal cells

Lymph node stromal cells are a heterogeneous population of cells, which can be divided into six subpopulations. Types of stromal cells differ in the expression of surface markers as a glycoproteins CD31 and podoplanin gp38 (FRCs – gp38+ CD31-, FDCs - gp38(+/-) CD31-, LECs - gp38+ CD31+, BECs - gp38- CD31 low, IAPs - gp38- CD31- ITGA+), production of small molecules, their localization and function. Most of them also express common markers of stromal cells such as desmin, laminin, various subunits of integrins, vascular cell adhesion molecule 1 (VCAM1) and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM1).

Fibroblastic reticular cells (FRCs)

FRCs are located in the T cell zone. They form a dense network that supports and guides the movement of DC, T and B lymphocytes. FRCs produce a reticular fibers rich in collagen, which forms a structure separate and distinct from the parenchyma of lymphoid tissue. Lymphocytes move along the fibers of these cells. Chemokines and antigens coming from lymph pass quickly through the reticular network to the T cell zone and HEVs. FRCs express chemokines such as CCL21 and CCL19. These molecules define the T cell zone, and support migration of T cells and DCs that carry the receptor CCR7. Furthermore, express components of extracellular matrix, such as the ER-TR7, fibrilin, laminin, fibronectin and intracellular components such as desminand α-actin smooth muscle. These molecules may influence the formation of network by FRCs. Eg. chemokine CCL21 is attached to the surface of the FRCs through a collagen and glycosaminoglycans. FRCs can be differentiated from other lymphoid stromal cells after obtaining expression of gp38.
FRCs are connected by fiber structure and create a conduit network. It consists of components of the extracellular matrix (ECM) produced FRCs. Conduits are composed of long fibers of collagen I. These are connected by collagen XIV, small leucine-rich proteoglycans and lysyl oxidase, which is also fixed the structure. This creates pores in the lymphoid tissue called a molecular sieve. Small molecules such as antigens and chemokines can quickly get through lymph node to lymphocytes in the T cell zone and B cell follicle or to BECs in HEVs.

Folicular dendritic cells (FDCs)

FDCs are localized in the center of B lymphocyte follicle. They form a dense network in which B lymphocytes are looking antigens. FDCs express Fc receptors (CD16, CD23 CD32), complement receptors (CD21 CD35) and complement components such as C4. These molecules facilitate the capture and presentation of naive antigen, particularly in the form of immune complexes on the surface of FDCs. FDCs support the development germinal center. There is an interaction between B cells FDCs and helper T lymphocytes. After the activation of B cells following their proliferation and differentiation into plasma and memory cells. FDRs promote migration of B lymphocytes to the primary B cell follicle due production of chemokine CXCL13 in the follicle.

Marginal reticular cells (MRCs)

MGRs form a layer just below the SCS. Allow you to bring antigens from SCS to B cell follicles thanks to their network organization. They specifically express a molecule TRANCE (RANKL), which belongs to the family of tumor necrosis factor. They are one of organizer cells involved in the formation of the structure of lymph node during organogenesis. On the edges of B cell follicles express CXCL13.

Lymphatic endothelial cells (LECs)

These endothelial cells line the lymphatic vessels. They express various adhesion molecules, chemokine CCL21, and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE 1), a homologue of CD44. These molecules provide the entry of hematopoietic cells into the lymphatic vessels. During inflammatory conditions, they extremely increase the amount of adhesion molecules on their surface that can bind more coming DCs from the lymph.

Blood endothelial cells (BECs)

They are specialized vascular endothelial cells. They line the inside of high endothelial venules (HEVs). They express the molecules as are a peripheral node adressin (PNAd) and chemokine CCL21. These molecules are essential for the entry of lymphocytes from the blood into the lymph nodes.

Integrin α7 pericytes (IAPs)

These cells express several types of integrin chains which generate various heterodimers. Integrins allow interaction with the hematopoietic cells, thus IAPs promote cell migration. To date this population is not enough explored.

Function of lymph node stromal cells

Lymph node stromal cells have primarily structural function. They form a scaffold for hematopoietic cells and support their movement. Furthermore they interact with hematopoietic cells and affect a development of the adaptive immune response. Their distribution and production of various molecules provide meeting and interaction of T lymphocytes, B lymphocytes and antigen presenting cells. This will allow the initiation of immune responses.

Development of the lymph node

Genesis of lymph nodes iniciate among the blood and lymphatic system. Interactions between stromal and hematopoietic cells are important for the development of lymph node. Crosstalk LEC, lymphoid tissue inducer cells and mesenchymal stromal organizer cells initiate a formation of lymph node nearby blood vessels.

Antigen delivery

An adaptive immune response takes place in the lymph node. To her opening required hematopoietic cells and antigens. The lymphocytes enter into the lymph node from HEVs through endothelial blood cells (see below). Antigens are collected from peripheral tissues and along with the lymph come into the lymph node by several afferent lymphatic vessels. Antigens are either soluble or presented on the surface DCs from peripheral tissues. Soluble antigens permeate passively through the LECs into lymph node. There are processed by resident APCs in the lymph node. DCs exhibit on their surface C-type lectin receptor (CLEC 2), which binds to gp38 on the surface of LECs. During inflammatory conditions, LECs increase the amount of adhesion molecules on their surface. Moreover, DCs on their surface express a CCR7 receptor. This interacts with a chemokine CCL21 produced by FRCs. DCs directed to the T-zone or B follicle along FRCs network due this interaction. Many APCs are accumulated near HEVS where can offer antigens on their surface for naive lymphocytes coming from blood.

Lymphocyte migration

Hematopoietic cells must get into contact with each other to lymphocytes become activated and initiate the immune response. Lymph node stromal cells provide meeting of hematopoietic cells. FRCs form a cellular network connected by conduits. Hematopoietic cells interact with the surface FRCs and move along the cellular network. Hematopoietic cells are directed to their destination in the lymph node. The movement is based on the environment of chemokines. This is due to the heterogeneous distribution by different types of stromal cells. Each type of stromal cells produces a specific range of chemokines as well as certain types of hematopoietic cells own the receptors for them. This provides sorting of hematopoietic cells in the target areas. So hematopoietic cells are organized found, interact with, and can be triggered the immune response. Naive T cells express the CCR7 receptor for the chemokine CCL21. After entering into the lymph node, T cells immediately interact with FRCs. T cells rapidly migrate along FRCs network into T cell zones where FRCs express chemokine CCL21. This signal serves for T lymphocytes to remain in the lymph node and search antigens. At first B cells also pass through the FRCs network and then they are directed to the B cell follicle. There FDCs produce chemokine CXCL13, for which B cells exhibit receptor CXCR5 on their surface. B and T cells leave the lymph node based on change in the concentration of sphingosine 1-phosphate (S1P), which haves the receptor. The concentration of S1P in the lymph node is maintained at a lower level than in the blood or in the lymph influence the activity of the S1P lyase.

Lymphocyte homeostasis

Millions of lymphocytes pass through the lymph node every day. They come from the thymus by HEVs (high endothelial venules). The inside of HEVs is consisted of blood endothelial cells (BEC). Adhesion molecules and chemokines are exhibited on surface of these cells. Lymphocytes are catch from blood due their bind to these molecules on BECs. BECs able to regulate the amount of entering cells. They contain a pocket in which can hold 4-5 lymphocytes. If necessary lymphocytes are release to lymph node. Lymphocyte homeostasis is ensured in the lymph node due to present cytokines. At least T cells are survived for eight weeks, since they left the thymus to their activating by antigen. This time is controlled by the presence of MHC class I on CD4 + T lymphocytes and MHC class II by CD8 + T lymphocytes. The cytokine IL-7 is another regulator. This cytokine is produced by FRCs and it promotes survival of resting T lymphocytes. Similarly, the B lymphocytes need a factor BAFF (B cell activating factor) for their survival, which is produced by FDCs. Effector cells penetrate into the efferent lymph vessel and they leave lymph node. They compensate dead peripheral lymphocytes and thus they maintain their constant level in the blood.

Peripheral tolerance

Autoreactive T cells are eliminated in the thymus by a process of clonal deletion. However, some of them are escaped. Lymph node stromal cells exhibit PTAs (peripheral tissue-restricted antigens) on their surface. PTAs are own molecules of the organism, which are abundant occur in peripheral tissues. Transcription factor Aire (autoimmne regulator) controls their expression. That is, population of cells called mTECs in the thymus. Lymph node stromal cells have very low levels of expression Aire. In contrast, they have a high level of expression of another transcription factor, called DF1. DF1 is a Aire-like transcription modulator. Each of them triggers the expression of other range of genes. This could explain that lymph node stromal cells exhibit other PTAs than cells in the thymus. CD8 + T cells that react with PTAs are deleted. These lymphocytes called autoreactive. In this way, lymph node stromal cells participated in maintaining of the peripheral tolerance.