Intravital imaging of T cell priming in the gut-associated lymphatic tissue (GALT)
Final Report Abstract
Multiple Sclerosis (MS) is an autoimmune disease which is characterized by inflammation in the central nervous system (CNS). Using an animal model of MS, experimental autoimmune encephalomyelitis (EAE), it has been demonstrated that infiltration and reactivation of CNS antigen-specific autoreactive T cells play a crucial role in the pathogenesis of the disease. These autoreactive T cells are found in healthy individuals but usually do not cause inflammation in the CNS. We hypothesized that the microbiota induce T cell stimulation in the intestine. Using calcium sensing protein as an activation marker of T cells in combination with intravital imaging, we demonstrate that autoreactive T cells receive priming from the microbiota in the ileal lamina propria. Consequently, the T cells acquire an inflammatory Th17 phenotype and initiate their infiltration to the CNS. The autoreactive T cells interact with other cells during their journey to the CNS and receive stimulation. Initially they acquire a migratory phenotype in the spleen and subsequently undergo reactivation in the CNS. However, the sources and mechanisms of this stimulation remained unclear. To address these questions, we employ Intravital imaging with calcium sensing protein to visualize the stimulation of T cells in different locations. The autoreactive T cells show short-lasting calcium signaling which is induced by chemokine signaling and may lead to the acquisition of a migratory phenotype. When the autoreactive T cells appear in the blood vessels at spinal cord leptomeninges, they do not show calcium signaling. Once they pass the blood-brain barrier, the autoreactive T cells exhibit long-lasting calcium signaling which is induced by local antigen-presenting cells (APCs) presenting endogenous autoantigen in the spinal cord leptomeninges before clinical onset and in the parenchyma during the acute phase. In summary, our project demonstrates that the microbiota induce inflammatory phenotype of the autoreactive T cells and following their infiltration to the CNS. In addition, we reveal that local APCs in the CNS activate the infiltrating autoreactive T cells. These steps are crucial for the pathogenesis of MS/EAE and can open new therapeutic targets.
Publications
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From classic to spontaneous and humanized models of multiple sclerosis: Impact on understanding pathogenesis and drug development. Journal of Autoimmunity, 54(2014, 11), 33-50.
Ben-Nun, Avraham; Kaushansky, Nathali; Kawakami, Naoto; Krishnamoorthy, Gurumoorthy; Berer, Kerstin; Liblau, Roland; Hohlfeld, Reinhard & Wekerle, Hartmut
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In vivo imaging in autoimmune diseases in the central nervous system. Allergology International, 65(3), 235-242.
Kawakami, Naoto
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Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy. Proceedings of the National Academy of Sciences, 114(31).
Kyratsous, Nikolaos I.; Bauer, Isabel J.; Zhang, Guokun; Pesic, Marija; Bartholomäus, Ingo; Mues, Marsilius; Fang, Ping; Wörner, Miriam; Everts, Stephanie; Ellwart, Joachim W.; Watt, Joanna M.; Potter, Barry V. L.; Hohlfeld, Reinhard; Wekerle, Hartmut & Kawakami, Naoto
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Intravital Imaging of T Cells Within the Spinal Cord. Methods in Molecular Biology (2018), 119-127. Springer New York.
Kawakami, Naoto
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Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity. Nature Immunology, 22(7), 880-892.
Hiltensperger, Michael; Beltrán, Eduardo; Kant, Ravi; Tyystjärvi, Sofia; Lepennetier, Gildas; Domínguez Moreno, Helena; Bauer, Isabel J.; Grassmann, Simon; Jarosch, Sebastian; Schober, Kilian; Buchholz, Veit R.; Kenet, Selin; Gasperi, Christiane; Öllinger, Rupert; Rad, Roland; Muschaweckh, Andreas; Sie, Christopher; Aly, Lilian; Knier, Benjamin; ... & Korn, Thomas
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Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two-photon imaging. Proceedings of the National Academy of Sciences, 120(30).
Bauer, Isabel J.; Fang, Ping; Lämmle, Katrin F.; Tyystjärvi, Sofia; Alterauge, Dominik; Baumjohann, Dirk; Yoon, Hongsup; Korn, Thomas; Wekerle, Hartmut & Kawakami, Naoto
