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Monitoring Cellular Movement in Vivo with Photoconvertible Fluorescence Protein ‘‘Kaede’’ Transgenic Mice

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Monitoring Cellular Movement in Vivo with Photoconvertible Fluorescence Protein ‘‘Kaede’’ Transgenic Mice Monitoring cellular movement in vivo with photoconvertible fluorescence protein ‘‘Kaede’’ transgenic mice Michio Tomura*, Naoki Yoshida†‡, Junko Tanaka†‡, Satoshi Karasawa§, Yoshihiro Miwa†‡, Atsushi Miyawaki§, and Osami Kanagawa*¶ *Laboratory for Autoimmune Regulation, Research Center for Allergy and Immunology, RIKEN, 1-7-22 Suehiro-cho, Tsurumi, Yokohama City, Kanagawa 230-0045, Japan; †Department of Molecular Pharmacology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; ‡PRESTO, Japan Science and Technology Agency, 5-Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan; and §Laboratory for Cell Function and Dynamics, Advanced Technology Development Center, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan Edited by Philippa Marrack, National Jewish Medical and Research Center, Denver, CO, and approved May 21, 2008 (received for review March 6, 2008) Kaede is a photoconvertible fluorescence protein that changes several organs and tissues, such as the thymus (14), mesenteric from green to red upon exposure to violet light. The photocon- lymph node, spleen (15), and leukocytes (16, 17). However, the version of intracellular Kaede has no effect on cellular function. direct injection of fluorescence substrate into organs inevitably Using transgenic mice expressing the Kaede protein, we demon- caused inflammatory reactions in the tissue. Thus, these meth- strated that movement of cells with the photoconverted Kaede ods have limited applications, and current technologies do not protein could be monitored from lymphoid organs to other tissues allow us to observe natural cellular movement in the body. In this as well as from skin to the draining lymph node. Analysis of the kind of situation, various genetically altered mouse lines and kinetics of cellular movement revealed that each subset of cells in mAbs specific to cell-surface molecules were established, and the lymph node, such as CD4؉ T, CD8؉ T, B, and dendritic cells, has new insights into cellular migration of the immune system in the a distinct migration pattern in vivo. Thus, the Kaede transgenic steady state and during immune response have been provided (4, mouse system would be an ideal tool to monitor precise cellular 5, 18, 19). However, almost all of those studies were done by movement in vivo at different stages of immune response to combination with a conventional cell transfer system, and in- pathogens as well as in autoimmune diseases. formation was limited to the general homing pattern of cells with no information on cellular emigration from tissue. Therefore, establishment of a novel system to track immune cells in mice will cell migration ͉ dendritic cells ͉ lymphocyte ͉ photoconvertible protein be an ideal tool for cell migration analysis, will contribute to visualization of cellular movement in the whole body, and will ymphocytes and other cells of the immune system are mobile clarify its molecular mechanisms. Land move around the whole body for surveillance (1). Here we report a system to monitor cellular movement in vivo Effective host defense against pathogens requires both innate with minimum manipulation of the transgenic mouse expressing and adaptive arms of the immune response (2, 3). The transition Kaede, a new photoconvertible fluorescence protein (20). Cells from the innate to the adaptive arm of the immune response is expressing Kaede can be marked by exposure to light without a critical step for the clearance of pathogens and is initiated by exerting any effects on cellular function. It is also possible to the interaction between antigen-presenting cells and a very small expose the lymph node and other organs to light with minimum number of antigen-specific T and B cells in lymphoid organs (2, manipulation. This system allows us to analyze cellular move- 3). For the successful interaction to establish effective immune ment in vivo, including both immigration and emigration of cells response, cooperative migration of antigen-presenting cells from in target organs. In an initial analysis of normal mouse, we inflammatory sites to the lymph node and recruitment of a demonstrated that cells are moving rapidly within lymphoid sufficient number of rare antigen-specific lymphocytes to the organs and some cells are migrating from nonlymphoid organs same lymph node are required (4, 5). Thus, the regulation of to lymphoid organs. Moreover, the migration of cells in vivo is regulated in a cell-type-specific manner in that each cell type, cellular movement in the body is vital to fighting infections. ϩ ϩ The development of the two-photon laser intravital micro- CD4 T, CD8 T, B, and dendritic cells, has a distinct replace- scope has enabled us to observe cellular movement in vivo (6, 7). ment rate in the lymph node. Thus, we believe that Kaede It has also enabled us to monitor interactions between dendritic transgenic mice can overcome many of the problems besetting cells and T cells, T cells and B cells, and other types of cells in previous technologies and can be used to monitor cellular various lymphoid organs. This instrument, when used with new movement in vivo during the generation and effector phase of IMMUNOLOGY methods to visualize different cells (8), is an important tool for protective immune response as well as the onset of the autoim- mune phenomenon. the analysis of immune responses in vivo. However, the two- photon laser intravital microscope is applicable to only a limited Results area of the organ of interest. Photoconversion of Kaede in Cells and in Transgenic Mouse. Kaede is Classical studies involving injection of ex vivo labeled cells into a photoconvertible GFP cloned from stony coral (20). Exposure animals have demonstrated the continuous recirculation of lymphocytes between the bloodstream and the lymph system (9, 10) and the dynamic changes in migration and emigration of cells Author contributions: M.T., Y.M., and O.K. designed research; M.T., N.Y., and Y.M. per- in lymphoid organs as well as in the circulation at various stages formed research; M.T., N.Y., J.T., S.K., Y.M., A.M., and O.K. contributed new reagents/ of immune response (11–13). However, this conventional cell analytic tools; M.T., Y.M., and O.K. analyzed data; and M.T. and O.K. wrote the paper. transfer system has limitations. Because of the low frequency of The authors declare no conflict of interest. transferred cells in host, it is difficult to use this system for small This article is a PNAS Direct Submission. populations, and this system cannot be applied to all cell types ¶To whom correspondence should be addressed. E-mail: [email protected]. because mechanical stress and/or incubation during cell isolation This article contains supporting information online at www.pnas.org/cgi/content/full/ and labeling processes ex vivo stimulate some type of cells. To 0802278105/DCSupplemental. overcome these problems, in situ cell labeling has been used for © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0802278105 PNAS ͉ August 5, 2008 ͉ vol. 105 ͉ no. 31 ͉ 10871–10876 Downloaded by guest on September 29, 2021 in their growth and reproduction. More importantly, expression of the Kaede protein and the photoconverting procedure had no effect on the homing capacity of both T and B cells to lymphoid organs (Fig. S3). Spleen cells from Kaede transgenic mice were exposed to violet light for 0, 5, and 10 min, and the cells were analyzed for the presence of red fluorescence and their capacity to proliferate in vitro. As shown in Fig. 1C, all cells had both red and green signals after exposure for 5 min because of the presence of both photoconverted and nonphotoconverted Kaede in the cells. After exposure for 10 min, some cells started to lose green fluorescence because of the loss of nonphotoconverted Kaede in the cells. Exposure of the cells to violet light for 5 or 10 min had no effect on their capacity to proliferate upon stimulation with Con A (T cells) or LPS (B cells) (Fig. 1D). Thus, we used a 5-min exposure of cells to violet light to convert Kaede in vivo throughout this study. Migration of Lymphocytes in Vivo in the Steady State. To monitor cellular migration in vivo, the inguinal lymph node was visualized by making a small incision on the skin and exposing it to violet light for 5 min. This procedure reproducibly converted 100% of the inguinal lymph node cells to express red fluorescence (Fig. 2A). In some experimental mice, the wound was surgically closed after photoconversion and lymph node cells were analyzed on days 1, 3, and 7. As shown in Fig. 2B, on day 1 after photocon- version, 76% of cells in the photoconverted inguinal lymph node had no photoconverted Kaede. Cells with photoconverted Kaede were found, albeit at a low percentage, in all lymphoid organs and peripheral blood. These results indicate that lymph node cells were rapidly replaced and migrated out to the whole body. It should be noted that, upon photoconversion of the inguinal lymph node, a large number of photoconverted cells were found in the ipsilateral axillary lymph node. When mice were treated with the sphingosine-1 phosphate receptor agonist FTY-720 (22, 23) after photoconversion of the inguinal lymph node, the appearance of photoconverted Kaede- Fig. 1. Photoconversion of Kaede in cells and in transgenic mice. (A) Kaede- expressing HeLa cells were photoconverted with UV light as described in negative cells in the inguinal lymph node and the number of Materials and Methods. The photoconverted Kaede signal was monitored for photoconverted Kaede-positive cells in other lymph nodes were the indicated times after photoconversion. (Scale bar: 30 ␮m.) (B) A neonatal drastically reduced (Fig. 2C). These results indicate that move- Kaede transgenic mouse (Upper) was exposed to violet light as described in ment of cells with photoconverted Kaede-positive cells in vivo Materials and Methods for indicated times (Lower) and observed with a reflects physiological immigration and emigration of cells in fluorescence stereoscopic microscope.
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