Mathematical Modeling Reveals Kinetics of Lymphocyte Recirculation in the Whole Organism

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.Author Summary: 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. Yet, the kinetics of lymphocyte entrance into and more importantly, residence times in these tissues still remain incompletely determined. 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. We find that lymphocytes on average must pass via vasculature of the lung or liver 20 times before they migrate to one of the secondary lymphoid tissues. Despite small size of capillaries in the lung and liver, we predict that on average lymphocytes spend less than 1 minute in the vasculature of these organs. Furthermore, we estimate that lymphocytes spend on average 2.5 hours in the spleen and 10 hours in the lymph nodes or Peyer's patches. Our mathematical modeling for the first time provides a quantitative, systems view of lymphocyte recirculation in the whole organism.