CD8+ T Cell-Mediated Mechanisms Contribute to the Progression of Neurocognitive Impairment in Both Multiple Sclerosis and Alzheimer's Disease?

Abstract

Neurocognitive impairment (NCI) is one of the most relevant clinical manifestations of multiple sclerosis (MS). The profile of NCI and the structural and functional changes in the brain structures relevant for cognition in MS share some similarities to those in Alzheimer's disease (AD), the most common cause of neurocognitive disorders. Additionally, despite clear etiopathological differences between MS and AD, an accumulation of effector/memory CD8+ T cells and CD8+ tissue-resident memory T (Trm) cells in cognitively relevant brain structures of MS/AD patients, and higher frequency of effector/memory CD8+ T cells re-expressing CD45RA (TEMRA) with high capacity to secrete cytotoxic molecules and proinflammatory cytokines in their blood, were found. Thus, an active pathogenetic role of CD8+ T cells in the progression of MS and AD may be assumed. In this mini-review, findings supporting the putative role of CD8+ T cells in the pathogenesis of MS and AD are displayed, and putative mechanisms underlying their pathogenetic action are discussed. A special effort was made to identify the gaps in the current knowledge about the role of CD8+ T cells in the development of NCI to "catalyze" translational research leading to new feasible therapeutic interventions.

Keywords: Alzheimer's disease; CD8+ tissue-resident memory T cells; effector/memory CD8+ T cells; microglia; multiple sclerosis; neurocognitive impairment.

Figure 1

Schematic representation of the putative interactions between (re)activated CD8+ T cells and microglia in the progression of multiple sclerosis (MS) and Alzheimer's disease (AD). It may be hypothesized that upon entering in damaged (by CD4+ T cells and neurotoxic oligomeric amyloid β peptides [Aβ]/tau protein in MS and AD, respectively) brain tissue, effector/memory (EM) CD8+ T cells reactivate and additionally activate microglia through Fas ligand/Fas-mediated interactions and secretion of potentially damaging proinflammatory cytokines (IFN-γ, IL-17, TNF-α, GM-CSF). Consequently, microglia change their functional properties, viz. initially predominantly protective (phagocyting damaging cells, and Aβ variants and their soluble and insoluble assembly) microglia change to become dysfunctional/detrimental secreting damaging mediators, including proinflammatory cytokines (IL-1β, TNF-α), reactive oxygen species (ROS), and reactive nitrogen species (RNS) on the account of phagocyting ability. To this microglial transition also contribute CD8+ tissue-resident memory T (Trm) cells, as they in the response to alterations in the local microenvironment [mirrored in increasing accumulation of various activating mediators, e.g., proinflammatory cytokines, local metabolites, including Aβ₁₋₄₂ and its soluble oligomers (o)Aβ₁₋₄₂, which are shown to interact with TLR2 expressed on their cell surface] transit from a suppressed state (sCD8+ Trm cell) maintained by PD-L1- and CD86-mediated signaling to activated proinflammatory cytokine-secreting state (aCD8+ Trm cell). The damaging mediators derived from (re)activated EM CD8+ T cells (including glutamate, which is shown to contribute to activation of extrasynaptic NMDA receptors to promote cell death) and microglia, along with toxic metabolites/mediators from neurons themselves (Aβ, glutamate), contribute to neuron/neurite damage and further progression of the diseases.