Lymphatics as Targets - New Tools to Regulate Traffic and Immunity in Health and Disease
Final Report Abstract
Lymphocytes continuously enter lymphoid organs, scan antigen presenting cells for their cognate antigen and in most cases, i.e. in the absence of immune activation, egress via the efferent lymph to re-start this cycle of events. In this project we analysed the dynamics of lymphocyte migration in particular focusing on lymphocyte egress into intestinal lymphatics and the cellular and molecular interactions underlying infection induced shutdown of Peyer’s patches (PP). To study lymphocyte egress, we established several new tools to label cells in situ, i.e. within lymphoid organs. Labelling of lymphocytes within PP was facilitated by injection of FITC, whereas photoconversion of fluorescent proteins was established as a versatile tool to label immune cells in all kinds of compartments. Studying the circulation dynamics of CD4 and CD8 T cells as well as gamma delta T cells, we showed that different T cell subsets acquire distinct migratory properties during their development and differentiation. Notably, this included a population of lymphoid organ-resident T cells that stayed in lymphoid organs without proliferation for prolonged time periods. The lymphoid organ resident phenotype of CD4, CD8 and gamma delta T cells correlated with low expression of the egress-promoting sphingosin-1-phosphate receptor 1 (S1PR1), suggesting that down-regulation of S1PR1 mediates lymphoid organ residency of lymphocytes. Previous work suggested that regulation of S1PR1 was dependent on CD69. However, studying the molecular pathways enabling retention of lymphocyte in organs, we observed two independent pathways: triggering of the T cell receptor initiated a CD69-dependent cascade of events resulting in down-regulation of S1PR1, as previously suggested in the literature. In contrast, block of lymphocyte egress from infected PP was independent of CD69. Thus, our results extended the canonical model of CD69-centered regulation of lymphocyte egress and indicate distinct layers of lymphocyte egress regulation.
Publications
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(2014). Hypertrophy of infected Peyer's patches arises from global, interferonreceptor, and CD69-independent shutdown of lymphocyte egress. Mucosal Immunol 7, 892-904
Schulz, O., Ugur, M., Friedrichsen, M., Radulovic, K., Niess, J.H., Jalkanen, S., Krueger, A., and Pabst, O
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(2014). Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure. Nature communications 5, 4821
Ugur, M., Schulz, O., Menon, M.B., Krueger, A., and Pabst, O.
