title: CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease.
abstract: We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1(G93A); abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA. kjjones1@iupui.edu.
authors.forename: Kathryn J
authors.identifier: http://orcid.org/0000-0002-0580-5436
authors.initials: KJ
authors.lastname: Jones
authors.affiliation: The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Chandler L
authors.initials: CL
authors.lastname: Walker
authors.affiliation: The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Sanders
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D009046:Motor Neurons / Q000276:immunology*; D009416:Nerve Regeneration / Q000276:immunology*; D000066829:Neuroprotection / Q000276:immunology*
keywords: ALS; Motoneurons; Neuroprotection; Neuroregeneration; T cells