Beers DR, Henkel JS, Zhao W, Wang J, Appel SH.
CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS.
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15558-63.
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T Cells to the Rescue
During inflammation, two parts of the immune system, the "innate" and the "adaptive," work hand in hand to defend against invading pathogens. The brain is harboring its own innate immune cells called glia cells, and these cells are activated in many neurodegenerative diseases such as ALS or Alzheimer disease. The activation of the brain's own innate immune cells is a double-edged sword. It can lead to neuroprotection, and frequently does so in acute injuries such as trauma or stroke. In a more chronic setting, such as neurodegenerative disease, the innate immune activation leads mainly to a detrimental outcome. The recent publication of the Appel lab now showed that a specific type of peripheral adaptive immune cells, the CD4+ T cells, enter the central nervous system in the mouse model of ALS. Once there, they seem to reprogram the local innate immune response. This leads to a more protective environment for the motor neurons, the cell type dying off in this dreadful disease. What is so astonishing about this finding is that the CD4+ cells only need to enter in a small number to produce a big effect. While still in early stages of discovery, this venue of research might open new ways for neuroprotection in ALS and other neurodegenerative diseases.
Amyotrophic lateral sclerosis (ALS) and Alzheimer’s might share important pathogenic pathways, and discoveries in one of these diseases or its animal models could therefore be important for the understanding of the other. Although considered a typical neurodegenerative disease mainly affecting motorneurons, ALS is often accompanied by T cell infiltration in the corticospinal tracts of patients. The significance of this T cell infiltration is not known. However, T cells have been demonstrated to secrete neurotrophic factors, and infusion of T cells specific for a myelin antigen has been demonstrated to protect against neurodegeneration after crush injury to the optic nerve and spinal cord (2).
In the current paper, the authors addressed the significance of CD4+ T cells in mice overexpressing mutant Cu2+/Zn2+ superoxide dismutase (mSODG93A), a widely used animal model for ALS. The mSODG93A mice develop a disease with many similarities to ALS, including T cell infiltration in the spinal cord. In this study, mSODG93A mice were bred with mice lacking recombination-activating gene 2 (RAG2), which is needed for developing functional T cells and B cells. The mSODG93A/RAG2-/- mice developed more rapidly evolving disease than mSODG93A mice. In contrast to mSODG93A with functional lymphocytes, no T cell infiltration occurred in the spinal cords of the mSODG93A/RAG2-/- mice. In a series of elegant experiments with bone marrow transplantation, the authors showed that infiltrating CD4+ T cells are neuroprotective and responsible for prolonged disease duration and survival. Bone marrow transplantation also restored the CD4+ T cell expression of neurotrophic factors. Concordant data was obtained with bone marrow transplantation to mSODG93A mice from mice lacking chemokine receptor 2 (CCR2), which is needed for T cell attraction. The infiltrating lymphocytes were CD4+ T helper cells; no B cells were observed and CD8+ cytotoxic T cells were only observed at very late stages.
How do these highly convincing data translate to human disease? This question is open to speculation, and although it is tempting to believe that the T cell infiltration observed in ALS patients is part of a reparative response to neurodegeneration, there are currently no observations in humans indicating that immune dysregulation plays a primary role in the development of ALS. T cell infiltration during early phases of ALS is extremely difficult to address, and has so far not been studied (3). Nevertheless, T cell-based therapies with glatiramer acetate (GA), an immunomodulator widely used for the treatment of multiple sclerosis, has been investigated in preclinical and early clinical trials in ALS (4,5). This drug induces an anti-inflammatory phenotype and production of substantial amounts of brain-derived nerve growth factor (BDNF) in GA-reactive T cells (6). Although the results of this therapy in humans have so far been disappointing, the results provided by Beers et al. support that T cells may be therapeutic targets in ALS. Moreover, it provides new molecular insight into the expanding field of protective immunology, showing that the T cells are not always the bad guys.