Abstract
The ability of lymphocytes to recirculate between blood and secondary lymphoid tissues such as lymph nodes (LNs) and spleen is well established. Sheep have been used as an experimental system to study lymphocyte recirculation for decades and multiple studies document accumulation and loss of intravenously (i.v.) transferred lymphocytes in efferent lymph of various ovine LNs. Yet, surprisingly little work has been done to accurately quantify the dynamics of lymphocyte exit from the LNs and to estimate the average residence times of lymphocytes in ovine LNs. In this work we developed a series of mathematical models based on fundamental principles of lymphocyte recirculation in the body under non-inflammatory (resting) conditions. Our analysis suggested that in sheep, recirculating lymphocytes spend on average 3 h in the spleen and 20 h in skin or gut-draining LNs with a distribution of residence times in LNs following a skewed gamma (lognormal-like) distribution. Our mathematical models also suggested an explanation for a puzzling observation of the long-term persistence of i.v. transferred lymphocytes in the efferent lymph of the prescapular LN (pLN); the model predicted that this is a natural consequence of long-term persistence of the transferred lymphocytes in circulation. We also found that lymphocytes isolated from the skin-draining pLN have a 2-fold increased entry rate into the pLN as opposed to the mesenteric (gut-draining) LN (mLN). Likewise, lymphocytes from mLN had a 3-fold increased entry rate into the mLN as opposed to entry rate into pLN. In contrast, these cannulation data could not be explained by preferential retention of cells in LNs of their origin. Taken together, our work illustrates the power of mathematical modeling in describing the kinetics of lymphocyte migration in sheep and provides quantitative estimates of lymphocyte residence times in ovine LNs.
Highlights
One of the peculiar properties of the mammalian adaptive immune system is the ability of its lymphocytes to recirculate between multiple tissues in the body; that is lymphocytes in the blood are able to enter the tissues and after some residence times in the tissues, they return to circulation [1]
The model predicted the existence of two recirculation compartments with average residence times of 2.4 and 19.5 h, with the latter compartment corresponding to lymph nodes (LNs) in the sheep
The model naturally explains the long-term decline in the number of labeled lymphocytes found in the efferent lymph of the cannulated prescapular LN (pLN) which is driven by the decline of labeled cells in the blood
Summary
One of the peculiar properties of the mammalian adaptive immune system is the ability of its lymphocytes to recirculate between multiple tissues in the body; that is lymphocytes in the blood are able to enter the tissues and after some residence times in the tissues, they return to circulation [1]. Antigen-unexperienced lymphocytes, primarily recirculate between secondary lymphoid tissues such as lymph nodes, spleen, and Peyer’s patches [2,3,4]. T Cell Residence Time lymphocytes which are able to access non-lymphoid tissues such as the skin and gut epithelium [2, 3, 5,6,7]. Because the frequency of lymphocytes specific to any given antigen is in general low and the place of entry of any pathogen is unknown by the naive host, recirculation of lymphocytes may increase the chance to that pathogen-specific cell will encounter its antigen [10, 11]. FTY720 prevents lymphocyte exit from lymph nodes, reducing their ability to recirculate [14,15,16]. Whether the side-effects of FTY720 is exclusively due to its impact on lymphocyte recirculation is unknown
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have