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CD4-Positive T Lymphocytes Provide a Neuroimmunological Link in the Control of Adult Hippocampal Neurogenesis¹

Susanne A. Wolf^2,*,, Barbara Steiner^2,*,, Akgul Akpinarli, Thomas Kammertoens^¶,||, Christina Nassenstein^#, Armin Braun^#, Thomas Blankenstein^¶,|| and Gerd Kempermann^3,*,**

^* Max Delbrück Center for Molecular Medicine, Research Group "Neuronal Stem Cells," Berlin-Buch, Germany, and Volkswagenstiftung Research Group, Department of Experimental Neurology, Charité University Medicine, Berlin, Germany; Institute for Anatomy, Department of Cell and Neurobiology, Zurich University, Zurich, Switzerland; Department of Neurology, Campus Virchow Klinikum, Charite University Medicine, Berlin, Germany; National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Cellular and Molecular Immunology, Bethesda, MD; ^¶ Max Delbrück Center for Molecular Medicine, Research Group "Molecular Immunology and Genetherapy," Berlin-Buch, Germany; ^|| Charite Institute of Immunology, Berlin, Germany; ^# Fraunhofer Institut for Toxicology and Experimental Medicine, Immunology and Allergology, Hannover, Germany; and ^** Center for Regenerative Therapies Dresden, Technische Universität, Dresden, Germany

Adult hippocampal neurogenesis occurs in an exceptional permissive microenvironment. Neuroimmunological mechanisms might be prominently involved in the endogenous homeostatic principles that control baseline levels of adult neurogenesis. We show in this study that this homeostasis is partially dependent on CD4-positive T lymphocytes. Systemic depletion of CD4-positive T lymphocytes led to significantly reduced hippocampal neurogenesis, impaired reversal learning in the Morris water maze, and decreased brain-derived neurotrophic factor expression in the brain. No such effect of CD8 or B cells was observed. Repopulation of RAG2^–/– mice with CD4, but not with CD8 cells again increased precursor cell proliferation. The T cells in our experiments were non-CNS specific and rarely detectable in the healthy brain. Thus, we can exclude cell-cell contacts between immune and brain cells or lymphocyte infiltration into the CNS as a prerequisite for an effect of CD4-T cells on neurogenesis. We propose that systemic CD4-T cell activity is required for maintaining cellular plasticity in the adult hippocampus and represents an evolutionary relevant communication route for the brain to respond to environmental changes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Volkswagenstiftung. B.S. is a Rahel Hirsch fellow of Charité, University Medicine Berlin.

² S.A.W. and B.S. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Gerd Kempermann, Genomics of Regeneration, Center for Regenerative Therapies Dresden, Tatzberg 47–49, 01307 Dresden. E-mail address: gerd.kempermann{at}crt-dresden.de

⁴ Abbreviations used in this paper: DG, dentate gyrus; BDNF, brain-derived neurotrophic factor; DCX, doublecortin; KO, knockout; MWM, Morris water maze; NGF, nerve growth factor.