Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis

Brain. 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074.

Abstract

Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Amyotrophic Lateral Sclerosis / blood
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Analysis of Variance
  • Animals
  • CD4 Antigens / metabolism
  • CX3C Chemokine Receptor 1
  • Cells, Cultured
  • Coculture Techniques / methods
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA-Binding Proteins / deficiency
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lectins / genetics
  • Lectins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia
  • Middle Aged
  • Mutation / genetics
  • RNA, Messenger / metabolism
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / pathology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • beta-N-Acetylhexosaminidases / genetics
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • CD4 Antigens
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Lectins
  • RNA, Messenger
  • Rag2 protein, mouse
  • Receptors, Chemokine
  • Toll-Like Receptor 2
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Chil3 protein, mouse
  • beta-N-Acetylhexosaminidases