Naive T cells that have migrated into lymph nodes but fail to recognize antigens and are not activated will eventually return to the bloodstream. This return to the blood completes one recirculation loop and provides the naive T cells another chance to enter secondary lymphoid organs and search for the antigens they can recognize. The routes of reentry of lymph into the blood are through the efferent lymphatics, perhaps via other lymph nodes in the same chain, and then through the lymphatic vasculature to the thoracic duct or right lymphatic duct, which then drain into the left or right venous angles, respectively, at the confluence of the left or right internal jugular and the subclavian veins. Lymph from most of the body drains through the thoracic duct, while lymph from the right arm, right thorax, and head drains through the right lymphatic duct.

The egress of naive T cells from lymph nodes is dependent on a lipid chemoattractant called sphingosine 1-phosphate (S1P), which binds to a GPCR family receptor on T cells called sphingosine 1-phosphate receptor 1 (S1PR1) (Fig. 1). S1P is present at higher concentrations in the blood and lymph than in tis sues. This concentration gradient is maintained because an S1P degrading enzyme, S1P lyase, is present in most tissues, so the lipid is catabolized in tissues more than in the lymph and blood. S1PR1 stimulates migration of cells up a gradient of S1P toward the lymph-filled medullary sinus and then efferent lymphatic. Circulating naive T cells have very little surface S1PR1 because the high blood concentration of S1P causes internalization of the receptor. After a naive T cell enters a lymph node, where S1P concentrations are low, S1PR1 reappears on the cell sur face over a period of several hours. This time lag allows a naive T cell to interact with APCs. If the naive T cell does not recognize any antigens before the S1PR1 receptor is reexpressed, the T cell is directed up the S1P concentration gradient into the efferent lymphatic, thereby leaving the lymph node, and eventually returns to the blood.

Fig1. Mechanism of egress of lymphocytes from lymphoid organs. S1P is present at a relatively high concentration in the blood and lymph and at lower concentrations within lymphoid tissues. Circulating naive T cells have low levels of S1PR1 because the receptor is internalized after binding S1P in the blood. Therefore naive T cells that have recently entered a lymph node initially cannot sense the S1P concentration gradient between the T-cell zone of the node and the lymph in the medullary sinus and efferent lymphatics, and these T cells cannot exit the node. After activation of a naive T cell by an antigen, surface expression of S1PR1 is blocked for several days and the activated cells also will not leave the node. S1PR1 is reexpressed after several minutes to hours in naive T cells, or days for activated and differentiated effector T cells, and these cells can then sense the S1P gradient and exit the node. The average dwell time in lymph nodes is about 12 hours for naive T cells and about 3 days for antigen-stimulated T cells, but this varies greatly in different conditions.

The egress from lymph nodes of effector T cells, generated from antigen-activated naive T cells, is also dependent on S1P. When a naive T cell is activated by an antigen in the lymph node, the surface expression of S1PR1 is suppressed for several days, and, therefore, the ability of the cells to leave the lymphoid organ in response to an S1P gradient is delayed. This suppression of S1PR1 is controlled in part by cytokines called type I interferons (IFNs) that are produced during innate immune responses to infections, as we will discuss in Chapter 4. Antigenic stimulation and IFNs together increase the expression of a protein called CD69, which binds to intracellular S1PR1 and reduces its cell surface expression. Thus, the activated T cell becomes transiently insensitive to the S1P gradient. This allows the antigen activated T cells to remain in the lymphoid organ and undergo clonal expansion and differentiation into effector T cells, a process that may take several days. When differentiation into effector cells is complete, the cells stop expressing CD69, and, therefore, S1PR1 is again expressed on the cell surface. At the same time, the newly generated effector cells reduce the expression of L-selectin and CCR7, which previously attracted the naive T cells to the lymph nodes. Therefore, the effector T cells become responsive to the concentration gradient of S1P, exit the lymph node via the medullary sinus draining into the efferent lymphatic, and eventually reenter the blood. S1P and the S1PR1 are also required for mature T-cell egress from the thymus and migration of B cell–derived plasmablasts from secondary lymphoid organs.

Our understanding of the role of S1P and S1PR1 in T-cell trafficking is based in part on studies of a drug called fingolimod (FTY720), which binds to S1PR1 and causes its downmodulation from the cell surface. Fingolimod blocks T-cell egress from lymphoid organs and thereby acts as an immunosuppressive drug. It is approved for the treatment of multiple sclerosis, an autoimmune disease of the central nervous system, and the use of fingolimod and other drugs with a similar mechanism of action to treat other autoimmune diseases and graft rejection is under investigation. Additional experimental evidence for the central role of S1P in naive T-cell trafficking comes from studies of mice with genetic ablation of S1PR1. In these mice, there is a failure of T cells to leave the thymus and populate secondary lymphoid organs. If naive T cells from S1PR1 knockout mice are injected into the circulation of other mice, the cells enter the lymph nodes but are unable to exit.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تقيم مجلس عزاء لإحياء ذكرى شهادة الإمام جعفر الصادق (عليه السلام)

بعد مرور أربع سنوات على تأسيسه قسم شؤون المعارف يعلن منجزات مركز التراث الإسلامي في إيران

قسم الشؤون الفكرية يختتم مسابقة (معز المؤمنين الثقافية) ويكرِّم الفائزين في كربلاء وبابل

قسم الصيانة ينفذ أعمالًا تطويرية في مجمع الإمام الهادي (عليه السلام)

المزيد

الآخبار الصحية

الشاشات ليست مجرد ترفيه.. تأثيرات طويلة المدى على دماغ طفلك

الأسباب الرئيسية لنقص الطاقة في الجسم

الكاكاو وتأثيره على العين.. نتائج واعدة من تجارب مخبرية

طبيب يحذر: أطعمة شائعة الاستهلاك أخطر على صحتنا من التدخين

المزيد

الآخبار التكنلوجية

باحثون في "نيويورك أبوظبي" يطورون تقنيات لرصد وعلاج الأورام

جيتكس إفريقيا.. المغرب يجمع "رواد التكنولوجيا" من 103 دول

طاقم أرتميس 2 يحطم رقما قياسيا ويستعرض الجانب البعيد للقمر

"أرتيميس 2" تنطلق حول القمر وتحطم الرقم القياسي

المزيد

مواضيع ذات صلة

Allergy and Hypersensitivity

The Antiviral Response

Migration of B Lymphocytes

Migration of Effector T Lymphocytes to Sites of Infection

Lymphocytes are Responsible for Acquired Immunity

The Major Proinflammatory Cytokines of Innate Immunity

Migration of Naive T Cells Into Lymph Nodes

Migration of Neutrophils and Monocytes to Sites of Infection or Tissue Injury

Leukocyte-Endothelial Interactions and Leukocyte Recruitment into Tissues

Formation of Pus

Feedback Control of the Macrophage and Neutrophil Responses

Macrophage and Neutrophil Responses During Inflammation