TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut

Romagnani, Andrea; Vettore, Valentina; Rezzonico-Jost, Tanja; Hampe, Sarah; Rottoli, Elsa; Nadolni, Wiebke; Perotti, Michela; Meier, Melanie A.; Hermanns, Constanze; Geiger, Sheila; Wennemuth, Gunther; Recordati, Camilla; Matsushita, Masayuki; Muehlich, Susanne; Proietti, Michele; Chubanov, Vladimir; Gudermann, Thomas; Grassi, Fabio; Zierler, Susanna

doi:10.1038/s41467-017-01960-z

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Journal article

TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut

Romagnani, Andrea Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Graduate School for Cellular and Biomedical Sciences, University of Bern, c/o Theodor Kocher Institute, Freiestrasse 1, P.O. Box 938, CH-3000 Bern 9, Switzerland
Vettore, Valentina Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Rezzonico-Jost, Tanja Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Hampe, Sarah Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Rottoli, Elsa Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Via G.B. Viotti 3/5, 20133 Milan, Italy
Nadolni, Wiebke Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Perotti, Michela Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Meier, Melanie A. Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Hermanns, Constanze Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Geiger, Sheila Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Wennemuth, Gunther Institute for Anatomy, Universitätsklinikum Essen, Hufelandstrasse 55, 45147 Essen, Germany
Recordati, Camilla Filarete Foundation, Viale Ortles 22/4, 20139 Milan, Italy
Matsushita, Masayuki Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Okinawa 903-0215, Japan
Muehlich, Susanne Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Proietti, Michele Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Center for Chronic Immunodeficiency, Universitätsklinikum Freiburg, Breisacher Street 115, 79106 Freiburg, Germany
Chubanov, Vladimir Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Gudermann, Thomas Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany
Grassi, Fabio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Via G.B. Viotti 3/5, 20133 Milan, Italy - Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, Via Francesco Sforza, 35-20122 Milan, Italy
Zierler, Susanna Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität München, Goethestrasse 33, 80336 Munich, Germany

04.12.2017

Published in:

Nature communications. - 2017, vol. 8, p. 1917

English The melastatin-like transient-receptor-potential-7 protein (TRPM7), harbouring a cation channel and a serine/threonine kinase, has been implicated in thymopoiesis and cytokine expression. Here we show, by analysing TRPM7 kinase-dead mutant (Trpm7 R/R) mice, that the enzymatic activity of the receptor is not essential for thymopoiesis, but is required for CD103 transcription and gut-homing of intra-epithelial lymphocytes. Defective T cell gut colonization reduces MHCII expression in intestinal epithelial cells. Mechanistically, TRPM7 kinase activity controls TGF-β-induced CD103 expression and pro-inflammatory T helper 17, but not regulatory T, cell differentiation by modulating SMAD2. Notably, we find that the TRPM7 kinase activity promotes gut colonization by alloreactive T cells in acute graft-versus-host disease. Thus, our results unravel a function of TRPM7 kinase in T cell activity and suggest a therapeutic potential of kinase inhibitors in averting acute graft-versus-host disease.

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