title: Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model.
abstract: Synucleinopathies comprise a group of neurodegenerative diseases associated with abnormal accumulation of α-synuclein. One of the key factors that contribute to the progression of synucleinopathies is neuroinflammation. However, the role of lymphocytes in synucleinopathies like Parkinson's disease (PD) remains largely unclear.
  
  
  
  To investigate how lymphocytes impact synucleinopathies, human wild-type α-synuclein (WTS) transgenic mice were crossed with mice lacking mature lymphocytes (Rag2(-/-)). In this in vivo model, we quantified α-synuclein aggregation in the substantia nigra (SN) and striatum and determined the numbers of innate and adaptive immune cells in the central nervous system (CNS). The activation state of resident and infiltrated CNS myeloid cells (M1 vs. M2) was further classified by gene and protein expression analyses. The impact of T and B lymphocytes on the phagocytic activity of microglia in the presence of α-synuclein aggregates was addressed in BV2 microglia in vitro.
  
  
  
  Compared to WTS(+) Rag2(+/+) mice, where T but not B lymphocytes infiltrated the CNS, decreased amounts of α-synuclein aggregates were found in WTS(+) Rag2(-/-) mice devoid of mature lymphocytes. The presence of T lymphocytes did not alter the number of Iba1(+) microglia but increased the frequency of the CD11b(+) CD45(hi) population in the CNS, indicative of an increased number of infiltrated macrophages. Moreover, the M1 phenotype was more prominent in WTS(+) Rag2(+/+) mice, whereas the M2 activation state was dominating in the absence of lymphocytes in WTS(+) Rag2(-/-) mice. In vitro, in the presence of T but not B lymphocytes, significantly less α-synuclein was phagocytosed by BV2 microglia, further supporting the prevalence of the M1 phenotype in the presence of T lymphocytes.
  
  
  
  Peripheral T lymphocytes strongly contribute to increased α-synuclein pathology via modulation of CNS myeloid cell function. In the presence of T lymphocytes, microglia phagocytosis of aggregated α-synuclein is reduced, which increases the severity of synucleinopathy.
authors.affiliation: IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Glückstrasse 6, 91054, Erlangen, Germany.|Bavarian Research Network on Induced Pluripotent Stem Cells ("ForIPS"), Erlangen, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Sommer
authors.affiliation: IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Glückstrasse 6, 91054, Erlangen, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fadler
authors.affiliation: IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Glückstrasse 6, 91054, Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Dorfmeister
authors.affiliation: Institute of Biochemistry (Emil-Fischer-Center), FAU Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany.
authors.forename: Anna-Carin
authors.initials: AC
authors.lastname: Hoffmann
authors.affiliation: Institute of Biochemistry (Emil-Fischer-Center), FAU Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Glückstrasse 6, 91054, Erlangen, Germany.|Bavarian Research Network on Induced Pluripotent Stem Cells ("ForIPS"), Erlangen, Germany.|Institute of Human Genetics, FAU Erlangen-Nürnberg, Schwabachanlage 10, 91054, Erlangen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.affiliation: IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Glückstrasse 6, 91054, Erlangen, Germany. iryna.prots@uk-erlangen.de.|Bavarian Research Network on Induced Pluripotent Stem Cells ("ForIPS"), Erlangen, Germany. iryna.prots@uk-erlangen.de.
authors.forename: Iryna
authors.initials: I
authors.lastname: Prots
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000276:immunology / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Adaptive immune system; Parkinson’s disease; Rag2; mThy1 WTS model