Understanding the Role of T Cells in CNS Homeostasis

• Published in: Trends in immunology Vol. 37; no. 2; pp. 154 - 165
• Main Authors: Ellwardt, Erik, Walsh, James T., Kipnis, Jonathan, Zipp, Frauke
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2016; Elsevier Limited
• Subjects: Allergy and Immunology; Alzheimer's disease; Amyotrophic lateral sclerosis; Animals; Antigens; Behavior; Brain-derived neurotrophic factor; Central Nervous System - immunology; Clinical trials; Dopamine; Homeostasis; Humans; Immune system; Lymphocyte Depletion; Lymphocytes; Neurodegeneration; Neurogenesis; Neurogenic Inflammation - immunology; Neurogenic Inflammation - therapy; Pathogenesis; Proteins; Regulation; Rodents; T cell receptors; T-Lymphocyte Subsets - immunology; T-Lymphocytes - immunology
• ISSN: 1471-4906; 1471-4981; 1471-4981
• DOI: 10.1016/j.it.2015.12.008

T cells within the central nervous system (CNS) have been generally considered pathogenic, especially in the context of neuroinflammatory disease. However, recent findings have revealed varied functions for T cells in the healthy CNS, as well as more complex roles for these cells in infection and injury than previously appreciated. Here we review evidence indicating important roles for different T cell subsets in the maintenance of CNS homeostasis. We examine the contribution of T cells in limiting inflammation and damage upon CNS injury, infection, and in neurodegeneration, and discuss the current understanding of the cellular and molecular mechanisms involved. Insight into these processes will shed light on the adverse effects of T cell-depleting therapies and present inroads into new therapeutic approaches for treating diseases affecting the CNS. T cells, found in the CSF of healthy subjects, maintain immune surveillance of CNS borders. If this function is antagonized, for example by natalizumab, opportunistic infections such as PML can occur. Upon recovery from encephalitis, T cells persist within the CNS after pathogens are no longer detectable. These T cells may prevent reinfection through key cytokine mediators – IFN-γ and TNF-α. Regulatory T cells prevent or counteract excessive CNS inflammation via CD39 and TIGIT, and use IL-10, TGF-β, or AMP as anti-inflammatory mediators. However, large numbers of Treg cells may suppress beneficial functions of conventional T cells after CNS injury, thus exacerbating neuronal death. Th2 cells have neuroprotective effects in stroke, Alzheimer's disease, and ALS. IL-4 production by CD4+ cells leads directly to axonal and neuronal survival via binding to IL-4 receptors expressed on neurons and potentiating neurotrophin signaling.