title: Ectonucleotidase activity and immunosuppression in astrocyte-CD4 T cell bidirectional signaling.
abstract: Astrocytes play a crucial role in neuroinflammation as part of the glia limitans, which regulates infiltration of the brain parenchyma by leukocytes. The signaling pathways and molecular events, which result from the interaction of activated T cells with astrocytes are poorly defined. Here we show that astrocytes promote the expression and enzymatic activity of CD39 and CD73 ectonucleotidases in recently activated CD4 cells by a contact dependent mechanism that is independent of T cell receptor interaction with class II major histocompatibility complex (MHC). Transforming growth factor-β (TGF-β) is robustly upregulated and sufficient to promote ectonucleotidases expression. T cell adhesion to astrocyte results in differentiation to an immunosuppressive phenotype defined by expression of the transcription factor Rorγt, which characterizes the CD4 T helper 17 subset. CD39 activity in T cells in turn inhibits spontaneous calcium oscillations in astrocytes that correlated with enhanced and reduced transcription of CCL2 chemokine and Sonic hedgehog (Shh), respectively. We hypothesize this TCR-independent interaction promote an immunosuppressive program in T cells to control possible brain injury by deregulated T cell activation during neuroinflammation. On the other hand, the increased secretion of CCL2 with concomitant reduction of Shh might promote leukocytes extravasation into the brain parenchyma.
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Fabia
authors.initials: F
authors.lastname: Filipello
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pozzi
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.|Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Michele
authors.initials: M
authors.lastname: Proietti
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Romagnani
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.|Hertie Institute for Clinical Brain Research, University of Tubingen, Department of Cellular Neurology, Tubingen, Germany.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mazzitelli
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.|CNR Institute of Neuroscience, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.|CNR Institute of Neuroscience, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Istituto Nazionale di Genetica Molecolare, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D001253:Astrocytes; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D006801:Humans; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D015720:5'-Nucleotidase
keywords: Immune response; Immunity; Immunology and Microbiology Section; T cell; astrocyte; calcium; ectonucleotidase; immunosuppression