The regulation of the exit of both naive and effector lymphocytes from secondary lymphoid organs by S1P is the basis for a new kind of potential immunosuppressive drug, FTY720 (fingolimod). FTY720 inhibits immune responses by preventing lymphocytes from returning to the circulation, thereby sequestering them in lymphoid tissues and causing rapid onset of lymphopenia (a lack of lymphocytes in the blood). In vivo, FTY720 becomes phosphorylated and mimics S1P as an agonist at S1P receptors. Phosphorylated FTY720 may inhibit lymphocyte exit by effects on endothelial cells that increase tight junction formation and close exit portals, or by chronic activation of S1P receptors, leading to inactivation and downregulation of the receptor.
9-8 T-cell responses are initiated in secondary lymphoid organs by activated dendritic cells.
Secondary lymphoid organs were first shown to be important in the initiation of adaptive immune responses by ingenious experiments in which a flap of skin was isolated from the body wall so that it had blood circulation but no lymphatic drainage. Antigen placed in the flap did not elicit a T-cell response, showing that T cells do not become sensitized in the infected tissue itself. Rather, pathogens and their products must be transported to lymphoid tissues. Antigens introduced directly into the bloodstream are picked up by antigen-presenting cells in the spleen. Pathogens infecting other sites, such as a skin wound, are transported in lymph via lymphatic vessels and trapped in the lymph nodes nearest
Fig. 9.13 Antigen-presenting cells are distributed by type in specific areas of the lymph node. dendritic cells are found throughout the cortex of the lymph node in the T-cell areas. Mature dendritic cells are by far the strongest activators of naive T cells, and can present antigens from many types of pathogens, such as bacteria or viruses as shown here. Macrophages are distributed throughout the lymph node but are concentrated mainly in the marginal sinus, where the afferent lymph collects before percolating through the lymphoid tissue, and also in the medullary cords, where the efferent lymph collects before passing via the efferent lymphatics into the blood. B cells are found mainly in the follicles and can contribute to neutralizing soluble antigens such as toxins.
Dendritic cells can be activated via their TLRs and other pathogen-recognition receptors (see Chapter 3), by tissue damage, or by cytokines produced during the inflammatory response. Activated dendritic cells migrate to the lymph node and express the co-stimulatory molecules that are required, in addition to antigen, for the activation of naive T cells. In the lymphoid tissues, these dendritic cells present antigen to naive T lymphocytes and prime antigen-specific T cells to divide and mature into effector cells that reenter the circulation.