Abstract
The kinetics of recirculation of naive lymphocytes in the body has important implications for the speed at which local infections are detected and controlled by immune responses. With a help of a novel mathematical model, we analyze experimental data on migration of 51Cr-labeled thoracic duct lymphocytes (TDLs) via major lymphoid and nonlymphoid tissues of rats in the absence of systemic antigenic stimulation. We show that at any point of time, 95% of lymphocytes in the blood travel via capillaries in the lung or sinusoids of the liver and only 5% migrate to secondary lymphoid tissues such as lymph nodes, Peyer's patches, or the spleen. Interestingly, our analysis suggests that lymphocytes travel via lung capillaries and liver sinusoids at an extremely rapid rate with the average residence time in these tissues being less than 1 minute. The model also predicts a relatively short average residence time of TDLs in the spleen (2.5 hours) and a longer average residence time of TDLs in major lymph nodes and Peyer's patches (10 hours). Surprisingly, we find that the average residence time of lymphocytes is similar in lymph nodes draining the skin (subcutaneous LNs) or the gut (mesenteric LNs) or in Peyer's patches. Applying our model to an additional dataset on lymphocyte migration via resting and antigen-stimulated lymph nodes we find that enlargement of antigen-stimulated lymph nodes occurs mainly due to increased entrance rate of TDLs into the nodes and not due to decreased exit rate as has been suggested in some studies. Taken together, our analysis for the first time provides a comprehensive, systems view of recirculation kinetics of thoracic duct lymphocytes in the whole organism.
Highlights
Lymphocytes, cells of the adaptive immune system, continuously recirculate between multiple tissues in the body [1,2,3]
It is has been well established that lymphocytes, major cells of the adaptive immune system, continuously recirculate between secondary lymphoid tissues in the body such as lymph nodes, spleen, and Peyer’s patches
Using previously published experimental data and a novel mathematical model we address this problem and estimate the rates of lymphocyte entrance into and exit from major secondary lymphoid tissues
Summary
Lymphocytes, cells of the adaptive immune system, continuously recirculate between multiple tissues in the body [1,2,3]. Effector and memory lymphocytes can access nonlymphoid tissues such as the brain, skin, lung, vaginal tract, salivary gland, and gut epithelium [6,7,8,9,10,11,12,13,14,15] Receptors and their ligands regulating entrance of lymphocytes into various lymphoid or nonlymphoid tissues have been thoroughly studied [16,17,18,19,20], how quickly lymphocytes can enter a particular tissue and how long they will stay in that tissue remains incompletely understood. It has been suggested that naive T cells have the ability to enter peripheral tissues such as gut lamina propria or the brain [6,23,24] but what regulates low recovered numbers of naive T cells in these tissues (e.g., a low entrance rate into the tissue or a high death rate in the tissue) remains unclear
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