title: CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles.
abstract: Monocyte-derived macrophages (mo-MΦs) and T cells have been shown to contribute to spinal cord repair. Recently, the remote brain choroid plexus epithelium (CP) was identified as a portal for monocyte recruitment, and its activation for leukocyte trafficking was found to be IFN-γ-dependent. Here, we addressed how the need for effector T cells can be reconciled with the role of inflammation-resolving immune cells in the repair process. Using an acute spinal cord injury model, we show that in mice deficient in IFN-γ-producing T cells, the CP was not activated, and recruitment of inflammation-resolving mo-MΦ to the spinal cord parenchyma was limited. We further demonstrate that mo-MΦ locally regulated recruitment of thymic-derived Foxp3(+) regulatory T (Treg) cells to the injured spinal cord parenchyma at the subacute/chronic phase. Importantly, an ablation protocol that resulted in reduced Tregs at this stage interfered with tissue remodeling, in contrast to Treg transient ablation, restricted to the 4 d period before the injury, which favored repair. The enhanced functional recovery observed following such a controlled decrease of Tregs suggests that reduced systemic immunosuppression at the time of the insult can enhance CNS repair. Overall, our data highlight a dynamic immune cell network needed for repair, acting in discrete compartments and stages, and involving effector and regulatory T cells, interconnected by mo-MΦ. Any of these populations may be detrimental to the repair process if their level or activity become dysregulated. Accordingly, therapeutic interventions must be both temporally and spatially controlled.
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Catarina
authors: C
authors: Raposo
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Nadine
authors: N
authors: Graubardt
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Merav
authors: M
authors: Cohen
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Chen
authors: C
authors: Eitan
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Anat
authors: A
authors: London
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors: Tamara
authors: T
authors: Berkutzki
authors: Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel michal.schwartz@weizmann.ac.il.
authors: Michal
authors: M
authors: Schwartz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D039521:CD11c Antigen / Q000235:genetics; D000073883:CX3C Chemokine Receptor 1; D004167:Diphtheria Toxin / Q000494:pharmacology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D009416:Nerve Regeneration / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014611:Vaccination
chemical_list: D015703:Antigens, CD; D039521:CD11c Antigen; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D019707:Receptors, Chemokine; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; C445081:myelin oligodendrocyte glycoprotein (35-55); D049452:Green Fluorescent Proteins
keywords: T cells; Th1; Treg; immune resolution; monocyte-derived macrophages; spinal cord injury