Effector T Cells in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) has long been considered a CD4 T-cell disease, primarily because of the findings that the strongest genetic risk for MS is the major histocompatibility complex (MHC) class II locus, and that T cells play a central role in directing the immune response. The importance that the T helper (Th)1 cytokine, interferon γ (IFN-γ), and the Th17 cytokine, interleukin (IL)-17, play in MS pathogenesis is indicated by recent clinical trial data by the enhanced presence of Th1/Th17 cells in central nervous system (CNS) tissue, cerebrospinal fluid (CSF), and blood, and by research on animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Although the majority of research on MS pathogenesis has centered on the role of effector CD4 T cells, accumulating data suggests that CD8 T cells may play a significant role in the human disease. In fact, in contrast to most animal models, the primary T cell found in the CNS in patients with MS, is the CD8 T cell. As patient-derived effector T cells are also resistant to mechanisms of dominant tolerance such as that induced by interaction with regulatory T cells (Tregs), their reduced response to regulation may also contribute to the unchecked effector T-cell activity in patients with MS. These concepts will be discussed below.

Figure 1.

Effector T cells in the central nervous system (CNS). Upon entry into the CNS, CD4 and CD8 effector T cells establish and/or maintain an inflammatory environment contributing to oligodendrocyte death, demyelination, and ultimately neuronal loss. Interleukin (IL)-17- and interferon γ (IFN-γ)-secreting cells activate local glia and antigen-presenting cells (APCs), up-regulating major histocompatibility complex (MHC) class I/II molecules on APCs, allowing them to restimulate myelin-reactive effector T cells. IL-17 promotes expression of proinflammatory cytokines IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor α (TNF-α). IFN-γ can directly kill oligodendrocytes. IL-17-secreting CD4 and CD8 T cells can secrete granzyme B, which kills neurons through the glutamate receptor (GluR3). CD8 T cells have cytolytic granules, comprising perforin and granzyme molecules, polarized toward demyelinated axons, and will release these for killing of oligodendrocytes and neurons.

Figure 2.

Effector T-cell mechanisms of resistance to regulation in multiple sclerosis (MS). Effector T cells can escape regulation by regulatory cells via a number of different mechanisms. Up-regulation of HLA-E on the surface of CD4 effector T cells interacts with the CD94/NKG2A inhibitory molecule on regulatory CD8 cells or regulatory natural killer (NK) cells to resist suppression. Further, down-regulation of CD155 and a concomitant decrease in DNAM-1 on the surface of NK cells also allows effector T cells to escape NK-mediated regulation. Increased interleukin (IL)-6 signaling and activation of STAT3 as well as secretion of granzyme B inhibits the capacity of CD4 FoxP3⁺ regulatory T cells (Tregs) to suppress effector T cells.