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Lymph node stromal cell
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<h2 id="structure">Structure</h2> <p class="note">Main article: <a href="/facts/Lymph_node/vkwfcQjH">Lymph node § Structure</a></p> <p>Lymph nodes are enclosed in an external <a href="/facts/Fibrous/ttkxAFBu">fibrous</a> <a href="/facts/Lymph_node_capsule/vkwfcQjH">capsule</a>, from which thin walls of sinew called <i>trabeculae</i> penetrate into the lymph node, partially dividing it. Beneath the external capsule and along the courses of the trabeculae, are <i>peritrabecular</i> and <i><a href="/facts/Subcapsular_sinus/vkwfcQjH">subcapsular sinuses</a></i>. These sinuses are cavities containing <a href="/facts/Macrophages/z7hkQu3o">macrophages</a> (specialised cells which help to keep the <a href="/facts/Extracellular_matrix/kaHC5Ez8">extracellular matrix</a> in order). </p><p>The interior of the lymph node has two regions: the <a href="/facts/Cortex_(anatomy)/cFCCqbUR">cortex</a> and the <a href="/facts/Medulla_of_lymph_node/vkwfcQjH">medulla</a>. In the cortex, lymphoid tissue is organized into <a href="/facts/Nodule_(medicine)/BgCs3GNE">nodules</a>. In the nodules, <a href="/facts/T_lymphocytes/5z6PQ9UN">T lymphocytes</a> are located in the <i>T cell zone</i>. <a href="/facts/B_cell/6Y1tgwwp">B lymphocytes</a> are located in the <i>B cell <a href="/facts/Lymph_follicle/vkwfcQjH">follicle</a></i>. The primary B cell follicle matures in <a href="/facts/Germinal_center/hdCfNIQc">germinal centers</a>. In the medulla are <a href="/facts/Hematopoietic/VRDwMymd">hematopoietic</a> cells (which contribute to the formation of the blood) and <a href="/facts/Stromal/31AA691H">stromal</a> cells. </p><p>Near the medulla is the <a href="/facts/Hilum_of_lymph_node/vkwfcQjH">hilum of lymph node</a>. This is the place where blood vessels enter and leave the lymph node and <a href="/facts/Efferent_lymphatic_vessel/jND0hlDu">lymphatic vessels</a> leave the lymph node. <a href="/facts/Afferent_lymph_vessel/jND0hlDu">Lymph vessels</a> entering the node do so along the perimeter (outer surface).<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <h2 id="function">Function</h2> <p>The lymph nodes, the <a href="/facts/Spleen/6NKn9d8s">spleen</a> and <a href="/facts/Peyer%2527s_patch/FvnKnk3r">Peyer's patches</a>, together are known as <a href="/facts/Lymphatic_system/yw5QLgMT">secondary lymphoid organs</a>. Lymph nodes are found between <a href="/facts/Lymphatic_duct/RHRb6B4u">lymphatic ducts</a> and blood vessels. Afferent lymphatic vessels bring <a href="/facts/Lymph/SL1xvRhq">lymph</a> fluid from the peripheral tissues to the lymph nodes.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> The lymph tissue in the lymph nodes consists of immune cells (95%), for example lymphocytes, and <a href="/facts/Stromal_cell/31AA691H">stromal cells</a> (1% to 5%)<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> The genesis of lymph nodes begins within the blood and the <a href="/facts/Lymphatic_system/yw5QLgMT">lymphatic system</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> Interactions between <a href="/facts/Stromal_cell/31AA691H">stromal</a> and <a href="/facts/Hematopoietic_cell/lf9GA0Dj">hematopoietic cells</a> are important for the development of <a href="/facts/Lymph_node/vkwfcQjH">lymph nodes</a>. <a href="/facts/Crosstalk_(biology)/VHU4wafm">Crosstalk</a> <a href="/facts/Lymphatic_endothelium/9yvaP7RJ">LEC</a>, lymphoid tissue inducer cells and mesenchymal stromal organizer cells initiate the formation of lymph nodes.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Naive lymphocytes (those with no history of contact with <a href="/facts/Antigen/9JlAernG">antigens</a>) travel from the <a href="/facts/Bone_marrow/4dfudk0H">bone marrow</a> or <a href="/facts/High_endothelial_venules/nPGl8J4v">high endothelial venules</a> of the <a href="/facts/Thymus/YYEJu7KA">thymus</a> where they develop as <a href="/facts/Lymphoblasts/vvsHz4ID">lymphoblasts</a>, to lymph nodes, where they mature.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p><p>The primary role of lymph node stromal cells is structural. They form a scaffold for hematopoietic cells and assist their movement along it. The molecular signaling systems (<a href="/facts/Chemokines/YrySj9eD">chemokines</a>) that distribute lymphocytes to appropriate localities within the lymph node (T and B cell segregation) are also created by lymph node stromal cells. Lymphocytes have receptors for such chemokines. For example, <a href="/facts/Naive_T_cell/QEl3A7Yh">Naive T cells</a> express the <a href="/facts/C-C_chemokine_receptor_type_7/zCeW23Aq">CCR7 receptor</a> for the chemokine <a href="/facts/CCL21/bfqhnjRD">CCL21</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> and B cells exhibit <a href="/facts/CXCR5/MdQA4JI5">CXCR5</a> receptors for chemokine <a href="/facts/CXCL13/XMbrGPuA">CXCL13</a>. </p><p>The lymph from the peripheral tissues contains soluble <a href="/facts/Antigen/9JlAernG">antigens</a> and arrives at the lymph node via <a href="/facts/Afferent_lymphatic_vessel/jND0hlDu">afferent lymphatic vessels</a>. An <a href="/facts/Adaptive_immune_response/bc7zT1Jo">adaptive immune response</a> takes place in response to the presence of the antigen in the lymph node. <a href="/facts/Antigen-presenting_cell/No0wr2uU">Antigen-presenting cells</a> accumulate near <a href="/facts/High_endothelial_venules/nPGl8J4v">high endothelial venules</a> to process soluble antigens. Antigens are also present on the surface of <a href="/facts/Dendritic_cells/19KBuKFK">dendritic cells</a>. </p><p>In an inflammatory state, lymphatic endothelial cells increase their surface adhesion molecules, and dendritic cells express a surface <a href="/facts/C-C_chemokine_receptor_type_7/zCeW23Aq">CCR7 receptor</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> This type of receptor interacts with the chemokine <a href="/facts/CCL21/bfqhnjRD">CCL21</a>, produced by <a href="/facts/Fibroblast/n08KsFll">fibroblastic</a> <a href="/facts/Reticular_cell/NLS7F8LM">reticular cells</a>. Due to this interaction, <a href="/facts/Dendritic_cells/19KBuKFK">dendritic cells</a> move to the T cell zone or to the B cell follicle along the fibroblast reticular cell network.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> <a href="/facts/Dendritic_cell/19KBuKFK">Dendritic cells</a> exhibit C-type lectin receptors (<a href="/facts/CLEC-2/sKv9nMGn">CLEC-2</a>), which bind to gp38 on the surface of lymphatic endothelial cells. </p><p>Lymphocytes leave the lymph node, as effector immune cells, via the <a href="/facts/Efferent_lymph_vessel/jND0hlDu">efferent lymph vessels</a>. Their numbers compensate for the removal of dead peripheral lymphocytes.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> B and T lymphocytes leave the lymph node based on changes in concentration of <a href="/facts/Sphingosine-1-phosphate/kLxX51Xx">sphingosine-1-phosphate</a> (S1P). The concentration of S1P in the lymph node is maintained at a level lower than that of the blood or the lymph under the influence of S1P lyase. This means immune cells may leave the lymph node along a chemokine gradient.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>Most T cells are, in time, eliminated in the <a href="/facts/Thymus/YYEJu7KA">thymus</a> by a process of <a href="/facts/Clonal_deletion/Atf9PeBI">clonal deletion</a>. However, some of them escape this process and are then "mopped up" in the lymph nodes. Lymph node stromal cells express peripheral tissue-restricted antigens (PTAs) on their surface. The <a href="/facts/Transcription_factor/wro0DPHe">Transcription factor</a> <i>Aire</i> (autoimmune regulator) that controls the expression of PTAs on mTEC cells in the thymus is only expressed at low levels by uncharacterized double negative stromal cells. Most lymph node stromal cells preferentially express DF1, an Aire-like transcription modulator.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="types-of-lymph-node-stromal-cells">Types of lymph node stromal cells</h2> <p>Lymph node stromal cells can be grouped into six sub-populations, known by their expression of <a href="/facts/Cell_adhesion_molecule/84EkpbAb">surface markers</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> The sub-populations include: fibroblastic reticular cells (FRCs); <a href="/facts/Follicular_dendritic_cells/lfvX5GcT">folicular dendritic cells</a> (FDCs); lymphatic endothelial cells (LECs); blood endothelial cells (BECs); alpha-7 integrin pericytes (AIPs); and double negative cells (DNCs). The surface markers include: <a href="/facts/Glycoprotein/bKPzzW7m">glycoprotein</a> <a href="/facts/CD31/yMKqNHdm">CD31</a> and glycoprotein <a href="/facts/Podoplanin/QSHJGJSr">podoplanin</a> GP38. The different sub-populations are also known by their production of small molecules; where they are located; and their function. Most also express common markers such as <a href="/facts/Desmin/vagwF65f">desmin</a>, <a href="/facts/Laminin/JTn5vrM4">laminin</a>, various subunits of <a href="/facts/Integrin/DNYUGbBp">integrins</a>, vascular <a href="/facts/Cell_adhesion_molecule/84EkpbAb">cell adhesion molecule</a> 1 (<a href="/facts/VCAM-1/I61XPDPh">VCAM-1</a>) and mucosal vascular addressin cell adhesion molecule 1 (<a href="/facts/MAdCAM-1/2jK0Yunj">MAdCAM-1</a>).<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> Surface markers<table><tbody><tr><th></th><th>CD 31 +</th><th>CD 31 -</th><th>GP 38 +</th><th>GP 38 -</th><th>ITGA7 +</th></tr><tr><th>FRC<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a></th><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>-</td></tr><tr><th>FDC</th><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>-</td></tr><tr><th>LEC</th><td>Yes</td><td>No</td><td>Yes</td><td>No</td><td>-</td></tr><tr><th>BEC</th><td>Low</td><td>-</td><td>No</td><td>Yes</td><td>-</td></tr><tr><th>AIP</th><td>No</td><td>Yes</td><td>No</td><td>Yes</td><td>Yes</td></tr><tr><th>DNC</th><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr></tbody></table> <h3>Fibroblastic reticular cells</h3> <p><a href="/facts/Fibroblast/n08KsFll">Fibroblastic</a> <a href="/facts/Reticular_cell/NLS7F8LM">reticular cells</a> (FRCs) are located in the T cell zone of the cortex. FRCs produce <a href="/facts/Collagen%2c_type_III%2c_alpha_1/lpFKHeyA">collagen alpha-1(III)</a> rich <a href="/facts/Reticular_fiber/rBp1kg3w">reticular fibers</a> that form a dense network within the lymphoid tissue. These are connected by <a href="/facts/Collagen%2c_type_XIV%2c_alpha_1/RY8xGoqh">collagen XIV</a>, small leucine-rich <a href="/facts/Proteoglycan/SFbGPK0R">proteoglycans</a> and <a href="/facts/Lysyl_oxidase/hjS3xW0T">lysyl oxidase</a>. The network of fibers supports and guides the movement of dendritic cells (DCs), T lymphocytes and B lymphocytes.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> It also creates a porous <i><a href="/facts/Molecular_sieve/Lzle8J7k">molecular sieve</a></i> in the lymph node. </p><p>The lymph carries <a href="/facts/Chemokines/YrySj9eD">chemokines</a> (molecular chemical messengers) and <a href="/facts/Antigen/9JlAernG">antigens</a> to the lymph node. At the lymph node, the lymph passes quickly through the reticular network to the T cell zone and the <a href="/facts/High_endothelial_venules/nPGl8J4v">high endothelial venules</a>. FRCs express chemokines such as <a href="/facts/CCL21/bfqhnjRD">CCL21</a> and <a href="/facts/CCL19/Qw07oxMl">CCL19</a> which assist the movement of T cells and dendritic cells with <a href="/facts/CCR7/zCeW23Aq">CCR7</a> receptors. </p><p>FRCs also produce components of extracellular matrix, such as ER-TR7, <a href="/facts/Fibrillin/37L6HchQ">fibrillin</a>, <a href="/facts/Laminin/JTn5vrM4">laminin</a>, <a href="/facts/Fibronectin/JrPv8TrU">fibronectin</a> and intracellular components such as <a href="/facts/Desmin/vagwF65f">desmin</a> and <a href="/facts/%25CE%2591-actinin/ozBJ72Y3">α-actin</a> smooth muscle that may influence the formation of the reticular fiber network.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> For example, the chemokine <a href="/facts/CCL21/bfqhnjRD">CCL21</a> attaches to the surface of the FRCs through <a href="/facts/Collagen/KsyAb72K">collagen</a> and <a href="/facts/Glycosaminoglycan/fo22ktAQ">glycosaminoglycan</a> molecules.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p>FRCs express cytokine <a href="/facts/Interleukin_7/IESzsYKr">IL-7</a>, a regulator of the survival of resting T lymphocytes. </p> <h3>Follicular dendritic cells</h3> <p><a href="/facts/Follicular_dendritic_cells/lfvX5GcT">Follicular dendritic cells</a> (FDCs) are found in the center of B lymphocyte follicles. They form a dense network of cellular filaments. They also express the <a href="/facts/Fc_receptor/hpv5q6Hu">Fc receptors</a>, <a href="/facts/CD16/BKv8e5FJ">CD16</a>, <a href="/facts/CD23/sdk79KrG">CD23</a> and <a href="/facts/CD32/SeYgD2sE">CD32</a>; the <a href="/facts/Complement_receptor/EsI570Ic">complement receptors</a> <a href="/facts/CD21/Y2IaYELw">CD21</a> and <a href="/facts/CD35/ShQaxyLT">CD35</a> and complement components. The network of cellular filaments and receptors help the FDCs capture antigens as immune complexes and present them to other immune cells. </p><p>FDCs assist the development of the <a href="/facts/Germinal_center/hdCfNIQc">germinal center</a> via an interaction with B lymphocytes and <a href="/facts/Helper_T-lymphocyte/nhwAYkDj">helper T-lymphocytes</a>. B lymphocytes proliferate and differentiate into <a href="/facts/Plasma_cell/1fY4bFHR">plasma cells</a> and <a href="/facts/Memory_B_cell/3Qaz8Pxd">memory cells</a>.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> FDCs produce chemokine <a href="/facts/CXCL13/XMbrGPuA">CXCL13</a> which promotes migration of <a href="/facts/B_lymphocyte/6Y1tgwwp">B lymphocytes</a> to the primary B cell follicle.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> B lymphocytes need a factor <a href="/facts/B-cell_activating_factor/pv7vFHum">B cell activating factor</a> (BAFF) for their survival, also produced by FDCs.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h3>Marginal reticular cells</h3> <p>Marginal reticular cells (MRCs) form a layer of cells beneath the <a href="/facts/Subcapsular_sinus/vkwfcQjH">subcapsular sinuses</a>. Via the reticular network, the MRCs bring antigens from the sub-capsular sinuses to the B cell follicles. MRCs express the molecule <i>TRANCE</i> (also known as <i><a href="/facts/RANKL/bggQcUcm">RANKL</a></i>), a type of <a href="/facts/Tumor_necrosis_factors/5G0MA0dG">tumor necrosis factor</a>. They are one of organizer cells involved in the formation of the structure of lymph node during <a href="/facts/Organogenesis/Wzd0g1al">organogenesis</a>. They express <a href="/facts/CXCL13/XMbrGPuA">CXCL13</a> at the edges of B cell follicles.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h3>Lymphatic endothelial cells</h3> <p><a href="/facts/Lymphatic_endothelium/9yvaP7RJ">Lymphatic endothelial cells</a> (LECs) line <a href="/facts/Lymphatic_vessel/jND0hlDu">lymphatic vessels</a>. They express <a href="/facts/Adhesion_molecule/84EkpbAb">adhesion molecules</a>, chemokine <a href="/facts/CCL21/bfqhnjRD">CCL21</a>, and lymphatic vessel endothelial hyaluronan receptor-1 (<a href="/facts/LYVE1/XdoqsEhd">LYVE1</a>), a homologue of <a href="/facts/CD44/A0hN9LtL">CD44</a>. These molecules allow the entry of hematopoietic cells into the lymphatic vessels.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> During an inflammatory state, the numbers of <a href="/facts/Adhesion_molecule/84EkpbAb">adhesion molecules</a> on the surfaces of LECs increase.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h3>High endothelial cells</h3> <p>High endothelial cells (HECs) are specialized vascular <a href="/facts/Endothelial_cell/L4ENFVnw">endothelial cells</a>. In the thymus, they line the <a href="/facts/High_endothelial_venules/nPGl8J4v">high endothelial venules</a> (HEVs) where lymphocytes originate. The HEVs of the lymph node express adhesion molecules like peripheral node addressin (PNAd) that are essential for the migration of naive T cells from the peripheral blood to the lymph node.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> In mouse lymph nodes the HECs also express the chemokine CCL21 which will bind its receptor CCR7 on the naive T-cell and enhance the migration.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> </p> <h3>Alpha-7 integrin pericytes</h3> <p><a href="/facts/ITGA7/ku6a0GE7">Alpha-7 integrin</a> <a href="/facts/Pericyte/2S2Y1vd4">pericytes</a> (AIPs) express several types of <a href="/facts/Integrin/DNYUGbBp">integrin</a> chains which generate <a href="/facts/Heterodimer/c8LwFJPG">heterodimers</a>. Integrin chains allow integrin pericytes to interact with hematopoietic cells and promote their migration.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h2 id="malignancy">Malignancy</h2> <p>Lymph node stromal cells can give rise to a number of malignancies including: follicular dendritic cell sarcoma; fibroblastic reticular cell sarcoma; inflammatory myofibroblastic tumours and others.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p><p>In addition, lymph node stromal cells may produce growth factors which actively contribute to tumour cell metastasis.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Malhotra, D; et al. (2013). "Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity". Immunol Rev. 251 (1): 160–176. doi:10.1111/imr.12023. PMC 3539229. PMID 23278748. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539229" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539229</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Mebius R. "Stromal immunology group inaugural meeting." Archived 2014-04-13 at the Wayback Machine British Society for Immunology website 15 March 2012. Accessed 20 March 2014. <a href="https://bsi.immunology.org/events--meetings/past-bsi-events/regional--affinity/--bsi-events-and-meetings-past-events-stromal-immunology-2011" target="_blank">https://bsi.immunology.org/events--meetings/past-bsi-events/regional--affinity/--bsi-events-and-meetings-past-events-stromal-immunology-2011</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Cihak R. "Anatomie." Grada publishing 1997, first edition. <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Bajenoff, M (2012). "Cells control soluble material and cellular transport in lymph nodes". Front Immunol. 3: 304. doi:10.3389/fimmu.2012.00304. PMC 3459003. PMID 23060882. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459003" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459003</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Malhotra, D.; et al. (2012). "Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks" (PDF). Nature Immunology. 13 (5): 499–510. doi:10.1038/ni.2262. PMC 3366863. PMID 22466668. <a href="https://www.immgen.org/ImmGenPublications/ni.2262ImmGen.pdf" target="_blank">https://www.immgen.org/ImmGenPublications/ni.2262ImmGen.pdf</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Bajenoff, M (2012). "Cells control soluble material and cellular transport in lymph nodes". Front Immunol. 3: 304. doi:10.3389/fimmu.2012.00304. PMC 3459003. PMID 23060882. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459003" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459003</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Malhotra, D; et al. (2013). "Stromal and hematopoietic cells in secondary lymphoid organs: partners in immunity". Immunol Rev. 251 (1): 160–176. doi:10.1111/imr.12023. PMC 3539229. PMID 23278748. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539229" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539229</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Malhotra, D.; et al. (2012). "Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks" (PDF). Nature Immunology. 13 (5): 499–510. doi:10.1038/ni.2262. PMC 3366863. 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