In a new paper, published in Immunity, Tal Arnon's group studied the movement of T cells in the spleen and for the first time has revealed one of the key steps in lymphocyte recirculation.
An effective adaptive immune system requires that lymphocytes continuously re-circulate between secondary lymphoid tissues of the body where they can "search" for pathogens, and potentially initiate immune responses. During times of homeostasis, access to these tissues is essential for allowing B and T cells to be "educated" by other specialized immune cells and to obtain signals that are presented inside these organs and are necessary for their survival. As such, a major goal in immunology has been to define the mechanisms and pathways that control the entry and egress of cells from these sites.
Over the last few decades, extensive studies provided a detailed understanding of how lymphocytes circulate thought lymph nodes and gut lymphoid structures and led to the development of therapeutic reagents designed to block cell recirculation through these sites in order to treat immunological disorders. However, the field has been far less successful in determining the routes and mechanisms of lymphocyte recirculation via the largest of the secondary lymphoid tissues, the splenic white pulp. Given that more cells pass through this tissue than via all other secondary lymphoid organs combined, understanding how cell traffic via the spleen remains an important challenge to address.
"Advances in live microscopy imaging have greatly improved our ability to analyse dynamic cell behaviour within the deep lymphoid compartments of the spleen," said Tal Arnon, Kennedy Trust of Rheumatology Research (KTRR) Senior Research Fellow and Wellcome Trust Investigator. "Using the technology we have been able to visualize T cell behaviour during entry into the spleen of live anesthetized mice and to directly explore this process in real time."
The work reveals a surprising passage of entry by T cells; after flowing out through branching blood vessels into the red pulp, cells join a procession that moves back along the outside of vascular structures, guiding them to the marginal zone bridging channels and into the T zone compartment. Attachment of T cells to these paths was sensitive to inhibitors that target Gi protein coupled receptors (GPCRs), but was independent of the chemokine receptor CCR7, suggesting a role for a yet unidentified GPCR during entry. Once attached, the cells moved in a one-directional manner towards T zones, a step which depended on CCR7 and which was enhanced by engagement of integrins. During inflammation, the chemotactic gradients along the perivascular paths were rapidly modified, leading to a temporary entry blockade.
Tal concluded "Our study reveals a key route of cell entry into this important organ and uncovers the extensive utility of the vasculature system in supporting intra-organ migration of circulating lymphocytes. It also shows that in contrast to previous hypothesises, entry and egress from the spleen are not mediated via the same route, thus predicting the existence of distinct, yet unidentified, egress sites. In future studies we aim to explore potential ways to address this point and to further define the molecular basis for cell entry and egress from the spleen. An important aspect of these efforts will be to determine how these factors change during immune responses, knowledge that may help to harness the enormous potential of the spleen for the development treatments and vaccines aiming to target the systemic immune response".
The study was funded by the Wellcome Trust Investigator Award and Kennedy Trust Senior Fellowship. It was a collaboration between researchers at Oxford University including Jens Rittecher, and Burkhard Ludewig from St Gallen University, Switzerland.