Abstract
Naive T lymphocytes exhibit extensive antigen-independent recirculation between blood and lymph nodes, where they may encounter dendritic cells carrying cognate antigen. We examine how long different T cells may spend in an individual lymph node by examining data from long term cannulation of blood and efferent lymphatics of a single lymph node in the sheep. We determine empirically the distribution of transit times of migrating T cells by applying the Least Absolute Shrinkage & Selection Operator () or regularised to fit experimental data describing the proportion of labelled infused cells in blood and efferent lymphatics over time. The optimal inferred solution reveals a distribution with high variance and strong skew. The mode transit time is typically between 10 and 20 hours, but a significant number of cells spend more than 70 hours before exiting. We complement the empirical machine learning based approach by modelling lymphocyte passage through the lymph node . On the basis of previous two photon analysis of lymphocyte movement, we optimised distributions which describe the transit times (first passage times) of discrete one dimensional and continuous (Brownian) three dimensional random walks with drift. The optimal fit is obtained when drift is small, i.e. the ratio of probabilities of migrating forward and backward within the node is close to one. These distributions are qualitatively similar to the inferred empirical distribution, with high variance and strong skew. In contrast, an optimised normal distribution of transit times (symmetrical around mean) fitted the data poorly. The results demonstrate that the rapid recirculation of lymphocytes observed at a macro level is compatible with predominantly randomised movement within lymph nodes, and significant probabilities of long transit times. We discuss how this pattern of migration may contribute to facilitating interactions between low frequency T cells and antigen presenting cells carrying cognate antigen.
Highlights
The anatomy of the immune system is unusual in that a number of its cellular components are motile
Estimating the Distribution of Transit Times in Blood The data analysed in this study were collected from sheep in which both blood and the efferent lymphatic from prescapular (15 data sets) or popliteal (2 data sets) lymph nodes were cannulated for a minimum of 100 hours
After infusion of labelled lymphocytes back into the circulation, blood and lymph samples were collected at various time intervals, and the proportion of labelled cells was analysed by flow cytometry
Summary
The anatomy of the immune system is unusual in that a number of its cellular components are motile. Recirculation of the lymphocyte pool is necessary so that rare, antigen-specific T lymphocytes have the best chance to encounter a dendritic cell (DC) carrying their cognate antigen. The vast majority of cells arrive at the LN via high endothelial venules (HEVs) and depart via the efferent lymphatics. Unless the T lymphocyte encounters an antigen specific for its receptor, the T lymphocyte will exit the LN via the efferent lymph vessels which drain into the principal lymphatic vessel, the thoracic duct, and continue their recirculation by re-entering blood flow. Most lymphocytes in afferent lymphatics are of effector phenotype, whereas naive (or central memory) predominate in efferent lymphatics. Since infection is often local, DC migration together with T cell recirculation maximises the chance that a naive T lymphocyte will locate its cognate antigen
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