T lymphocytes are blood cells that carry out the main functions of our immune system. Dendritic cells and B lymphocytes are other types of immune cells that present foreign substances (such as microbial proteins) and “self” substances from our own tissues to T lymphocytes. In this way, T lymphocytes are “educated” to distinguish between self and non-self, so they can mount an immune response to pathogens but recognize and remain tolerant of one’s own bodily tissues. When this system fails to operate properly, autoimmune disease and immune deficiencies can result. Recent medical breakthroughs have shown that when a patient has leukemia or other forms of cancer, the patient’s T lymphocytes can be isolated, genetically engineered and infused back into the patient, so that they can recognize and attack the patient’s cancer cells. Thus, T lymphocytes are key players in the revolutionary strategy of cancer immunotherapy.
T lymphocytes undergo maturation in the thymus, a small gland located just above the heart, and are then released into the bloodstream. T lymphocyte egress from the thymus is essential for immune surveillance and to fight various types of infections. Sphingosine-1-phosphate (S1P) is a lipid molecule found at high levels in the blood and low levels in most tissues. Mature T cells produce a cell surface receptor that recognizes S1P, allowing the S1P chemical gradient to attract them into the bloodstream once they have completed their education in the thymus. However, the precise mechanisms that control T lymphocyte egress are not fully understood.
Our research has unveiled a novel role of thymic dendritic cells, namely the metabolism of S1P at the site of mature T cell egress from the thymus. We showed that thymic dendritic cells take up S1P and metabolize it through the actions of an enzyme called S1P lyase, generating a localized S1P gradient that facilitates T lymphocyte egress into the blood. Thus, in addition to their well-established role in antigen presentation and immune tolerance, dendritic cells also act as metabolic gatekeepers of lymphocyte trafficking. In light of the fact that dendritic cells are known to continually traffic throughout the body surveying for the presence of infectious agents, our observations raise the possibility that dendritic cells could potentially control the release of T lymphocytes in response to various disease states or conditions. These findings provide a deeper understanding of how the body regulates lymphocyte trafficking and could result in novel strategies to treat a variety of conditions including autoimmune diseases, immune deficiencies, prematurity, infections, cancer, and the loss of immunity after bone marrow transplantation. Our study appeared in the ‘Journal of Experimental Medicine (October 17, issue) published by Rockefeller University Press.
Kumar A, Zamora-Pineda J, Suh JH, Zhang M, Saba JD. Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress. J Exp Med. 2016 Nov 14;213(12):2773-2791.
Tuesday, July 10, 2018 10:28 AM