title: Regulatory T cells in central nervous system injury: a double-edged sword.
abstract: Previous research investigating the roles of T effector (T(eff)) and T regulatory (T(reg)) cells after injury to the CNS has yielded contradictory conclusions, with both protective and destructive functions being ascribed to each of these T cell subpopulations. In this work, we study this dichotomy by examining how regulation of the immune system affects the response to CNS trauma. We show that, in response to CNS injury, T(eff) and T(reg) subsets in the CNS-draining deep cervical lymph nodes are activated, and surgical resection of these lymph nodes results in impaired neuronal survival. Depletion of T(reg), not surprisingly, induces a robust T(eff) response in the draining lymph nodes and is associated with impaired neuronal survival. Interestingly, however, injection of exogenous T(reg) cells, which limits the spontaneous beneficial immune response after CNS injury, also impairs neuronal survival. We found that no T(reg) accumulate at the site of CNS injury, and that changes in T(reg) numbers do not alter the amount of infiltration by other immune cells into the site of injury. The phenotype of macrophages at the site, however, is affected: both addition and removal of T(reg) negatively impact the numbers of macrophages with alternatively activated (tissue-building) phenotype. Our data demonstrate that neuronal survival after CNS injury is impaired when T(reg) cells are either removed or added. With this exacerbation of neurodegeneration seen with both addition and depletion of T(reg), we recommend exercising extreme caution when considering the therapeutic targeting of T(reg) cells after CNS injury, and possibly in chronic neurodegenerative conditions.
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908; Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: James T
authors.initials: JT
authors.lastname: Walsh
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908; Institute of Neurosciences, Fourth Military Medical University, Xi'an 710038, China;
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: Igor
authors.initials: I
authors.lastname: Smirnov
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lorenz
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908; and Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Tung
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908; Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908; kipnis@virginia.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002470:Cell Survival; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000276:immunology* / Q000473:pathology; D020221:Optic Nerve Injuries / Q000276:immunology* / Q000473:pathology; D012160:Retina / Q000276:immunology* / Q000293:injuries / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation