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 (SOD1G93A; 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.

Aberrant ER Stress Induced Neuronal-IFNβ Elicits White Matter Injury Due to Microglial Activation and T-Cell Infiltration after TBI

“…The recent findings of Ndode-Ekane et al 2018suggests that acute infiltration of T cells into the brain parenchyma after TBI is a contributing factor to poor post-injury recovery. On the other hand, in other models of CNS injury, T cells have been found to confer neuroprotection (Moalem et al, 1999;Jones et al, 2015). Thus, it remains unclear what role(s) T-lymphocytes play in post-TBI functional outcome, secondary inflammatory processes, and trauma-associated wound-healing responses.…”

Synaptic Plasticity on Motoneurons After Axotomy: A Necessary Change in Paradigm

“…The diversity of reported effects on synaptic coverage after altering the astrocytic reaction around axotomized motoneurons could be explained considering two sequential roles for astrocytes. First, during the regenerative phase (when the axon is growing in the peripheral nerve) enlarged astrocytes isolate pre and postsynaptic surfaces preventing synapse re-formation, and also providing trophic support (Tyzack et al, 2014;Jones et al, 2015). Second, after motor axons reinnervate muscle, astrocytes withdraw their processes exposing motoneuron surfaces that then become available for synaptogenesis actively promoted through TSP-1.…”

“…Similarly, studies in the cerebral cortex suggest that somatic wrapping of neurons by lipopolysaccharide (LPS)-activated microglia is neuroprotective through a mechanism that involves the removal of perisomatic GABA synapses and upregulation of anti-apoptotic genes (Chen et al, 2014). In contrast, inhibitory synapses are generally preserved over axotomized motoneurons and any neuroprotective role for microglia is at present controversial (reviewed in Aldskogius, 2011, but see Jones et al, 2015 andTanaka et al, 2017). Regardless of the exact roles played by inhibitory synapses, MHC-I and TLRs have emerged as key modulators of inhibitory synapse plasticity after axotomy, potentially through microglia actions.…”

Emerging Roles for the Immune System in Traumatic Brain Injury

“…In other models of CNS injury, T cells have been found to confer neuroprotection (60–62). For example, Walsh et al recently reported that protection after spinal cord injury (SCI) is guided by specific T cell-derived cytokines, particularly IL-4 (63).…”